Wade M Chumney
email: wade.chumney@csun.edu

David M Wasieleski
email: wasieleski@duq.edu

E Günter Schumacher
email: gunter.schumacher@icn-groupe.fr

The Conflict between U.S. Patent Protection and Technological Innovation: Analysis and Problem Solving by Means of the Integrated Causal Model for Innovated Ethic

Keywords: Patent Law, Innovation, Integrated Causal Model

Criticisms of patent laws for technological innovations in the U.S. reveal a multifaceted milieu of problems centered around the protection of short-term economic gain and individual property rights. In this paper, we consider this a conflict between current patent laws and the innovation capabilities of organizations. We propose a solution that enables the company to assure its long-term survival in the face of these restrictions. This presumes that the firm will at least maintain its innovation capacities while preserving the company's ethical values and those of its social environment. We offer a theoretical model that is designed to help managers and policy-makers reorient their governance strategies for managing the innovation process, using the "ethics of responsibility," which establishes the link to individual moral values at the beginning of a governance process as well as the consequences of a decision. Our Integrated Causal Model of Ethical Innovation for patents is presented and implications for global organizations and possible solutions for patent law process failure are offered.

Are we entering a crisis of technological innovation? The Economist has reported that in the coming decade the rate of innovation may actually slow globally despite an increased rate of social and technological acceleration [START_REF] Greene | Has the idea machine broken down?[END_REF]. While there are numerous reasons cited for this phenomenon, there is a growing concern among intellectual property scholars and business practitioners that existing patent laws actually inhibit technological innovations, which runs counter to the very purpose of patent systems [START_REF] Thomas | Debugging software patents: Increasing innovation and reducing uncertainty in the judicial reform of software patent law[END_REF]). Google's Senior Vice President of Corporate Development and Chief Legal Officer, David Drummond, stated that the current patent system will curb his company's ability to innovate (Greene August 3, 2011).

Criticisms of patent laws for technological innovations reveal a multi-faceted milieu of problems centered on the protection of short-term economic gain [START_REF] Shu | The long term impact of business cycles on innovation: Evidence from the Massachusetts Institute of Technology[END_REF]. While attempts to reform patent laws have been undertaken (the Leahy-Smith America Invents Act), further proposals may place innovation at risk. In this present paper, we consider this a conflict between current U.S. patent policies and the innovation capabilities of organizations.

In the United States, the number of filed patents in their respective patent offices has increased dramatically since 2000 (Rentocchini 2010). However, this increased filing of patent applications should not be confused with increased innovation in the U.S. Economy. As Boldrin and Levine note:

The case against patents can be summarized briefly: there is no empirical evidence that they serve to increase innovation and productivity, unless productivity is identified with the number of patents awarded-which, as evidence shows, has no correlation with measured productivity. This disconnect is at the root of what is called the "patent puzzle": in spite of the enormous increase in the number of patents and in the strength of their legal protection, the US economy has seen neither a dramatic acceleration in the rate of technological progress nor a major increase in the levels of research and development expenditure [START_REF] Boldrin | The Case Against Patents[END_REF].

In general, laws embody ethical norms and establish the rules upon which business is expected to operate (Carroll 1979: 500). Consequently, law can serve as a referent institution to society's consensual moral norms (Christensen 2007: 456). Intellectual property laws embody societal norms within the domain of innovation and the world of business. As legal systems always reflect a specific national or international culture with its moral value system, it seems to us evident that this conflict implies also an ethical component. So the current US patent law appears to reflect a societal value system or, to be more precise, a balancing/weighting of societal ethical values, which manifestly is no longer compatible with the property of today's technological innovation. This conflict between current US patent law and technological innovation illustrates for us one of numerous cases of apparent innovation-ethic incompatibility.

This incompatibility is neither of a general nature nor is it a permanent fact, which has been recently shown by Schumacher & Wasieleski and their Integrated Causal Model (ICM) on ethic and innovation (Schumacher&Wasieleski 2013). In this paper we will apply this ICM-model, initially developed for the analysis of decision-making in organizations (meso-level), to the level of society (macro-level) with its typical decision makers (politicians, legislators, judges, etc.). This adaptation will include a stronger focus on the dynamic potential of the model, which not only reveals compatibilities and incompatibilities in this field, but also analyzes the genesis/evolution of the problem and the solutions proffered for the future.

In order to understand the ICM, its adaptation to the macro-level, and the particular issue of patents on technological innovation, it is necessary to clarify some terms. At first we will distinguish the definitions of "ethic" and of "ethics", which form the base of our analysis. Ethic will be referred to as a system of moral attitudes and behaviors encompassing concepts, standards and rules which find their expression in informal elements of organizations (customs, manner, tradition) as well as in formal, written elements of organizations (codes, laws, contracts). In effect, ethic is another term for a moral system. Adopting this perspective it becomes evident that patent laws also reflect the ethical values system of a particular society.

Ethics, on the other hand, will be referred to as a systematic, conceptual way of thinking on an ethic, which may be realized descriptively or normatively and which is predominantly carried out within an academic discipline (i.e., business ethics).

Another central notion refers to the concept of "innovation". We employ this term (and its derivations) on two different levels. On one hand the term "innovation" will designate the subject of patent law in the form of a new process or a new product to be patented. On the other hand, we will use the term "innovation" in order to describe the process and the result of new legislation and to name a rebalanced ethical value system with its underlying new justification in a form of a new ethics.

At the macro-level, the ICM can help policy-makers analyze which innovations in legislation and their corresponding ethical justification (ethics) are necessary in order to make product and process innovation in a society that are compatible with the societal value system. Such analysis can also remove innovation obstacles rooted in a rigid, antiquated moral system.

As the paper will show, modification of laws and ethics over time does not mean automatically abandoning a former ethical value mix, but can also reflect a new way to remain loyal to a "traditional" societal value system within a changing society. If the policy maker succeeds in their reform efforts, he/she will liberate the product or process innovation-projects from a rigid ethical context, called "fossilizing ethic" in the ICM. Next, he/she will participate via legal modifications in expressing a new moral value set that is based on a new ethics, thereby creating an "innovated ethic". At the end, of this reform process he/she permits the realization of the initially blocked product or process innovation, so that this innovation cannot only emerge, but also be compatible with the ethical value set of the society. This innovation is known as an "ethical innovation" in our ICM-model. The "innovated ethic", which will provide the solution for the conflict between U.S. patent law and technological innovation, encompasses two levels: a) the modification of law (factual level) and b) the modification of the justifying ethics (conceptual level).

Our theoretical model is designed to help managers and policy-makers reorient their governance strategies for managing the innovation process. It further explains under what conditions innovation with a solid ethical substrate is likely, and under what conditions it is not.

Ethical innovation refers to the duality of a corporate innovation outcome-orientation coupled with institutionalized ethical control mechanisms. Firms that demonstrate this combination of outlook and process are more likely to enable long-term innovations. Since our model analyzes the relation between ethic and innovation, the solution to the aforementioned conflict requires an empirically oriented observation of ethic-innovation links, as well as a tool for choosing a specific theoretical ethical framework-an ethics-which would then permit us to elaborate on an ethically based solution for the managers. Such an ethics should -in order to take into consideration companies that interact with both the private and societal spheres -encompass all three levels (individual, corporate, society).

Our analysis of the "patent-versus-innovation" problem would be incomplete if one dimension, already strongly underlined in the Integrated Causal Model and included in the concept of responsibility, would be neglected: the dimension of time. It is assumed that firms must innovate in order to survive. Indeed, the firm's survival objective, resulting from a longterm orientation, and the immediate consequences associated with responsibility all imply the existence of a temporal component. As developed later in this paper, the proposed legal reform will focus on the time dimension, as there is no doubt that our stated patent/innovation problem is also due to incongruent time periods: the short life cycle of some type of innovations and the long duration of patents in global companies. In order to address this time dimension adequately within the discussion of a potential law reform (factual level of the innovated ethic) we will refer to Hartmut Rosa's Theory of Acceleration (2009). This theory offers the possibility of distinguishing between the time factor and the ethical factor as the two main causes for the current patent/innovation problem. Ontologically, this fits nicely with our Integrated Causal Model (ICM) for Ethical Innovation.

Concerning the conceptual level of the innovated ethic, i.e. the question which ethics is the foundation of the U.S. patent law system and to which degree a new ethics is necessary to justify legal modifications, this paper will show how a certain balance of deontological and utilitarian ethics has created an historical value-mix (property rights and common good). The ethics of responsibility could provide an updated ethics for legal modifications in U.S. Patent law. First formulated explicitly by Max [START_REF] Weber | The Theory of Social and Economic Organization 1 st American Edition[END_REF], and more recently reformulated and linked to the environmental challenges of the twenty-first century by German philosopher, Hans [START_REF] Jonas | The Imperative of Responsibility: In Search of Ethics for the Technological Age[END_REF], the ethics of responsibility does not limit its approach to the element of duty, but takes the consequences of a decision as the final evaluation criterion for an ethical success or failure. Thus, it allows analysis beyond the sterile opposition between deontology and consequentialism. In his 2009 Society for Business Ethics Presidential Address, Rob Phillips asks the business ethics field to reconsider issues related to responsibility in organizations [START_REF] Phillips | Ethics and network organizations[END_REF]. He acknowledges that social controls are useful governing mechanisms, "particularly where legal controls are ambiguous or ineffective" (541), which we argue is true for current patent protections.

The structure of the paper is as follows:

We begin our discussion by first introducing the ethics of responsibility which will serve as the normative foundation of our argument related to the revision of the patent law process.

Then, this ethics is discussed in the context of intellectual property issues. This includes a discussion of the foundational values underlying the U.S. patent system (conceptual level of current ethic in this field). We will show that the ethics of responsibility can be realized pragmatically in patent law applications. This transitions into a specific discussion of the ethics behind patent processes for corporations. Given our argument's emphasis on the time dimension related to long-term ethical innovation, the concept of time in modernity is presented (factual level of the innovated ethic). Finally, once all of these elements are laid out, our Integrated Causal Model of Ethical Innovation for patents is posited. Implications for organizations and possible solutions for patent law process failure are offered.

Ethics of Responsibility

Business ethicists have been conflicted for years about what ethical standards to apply to organizations conducting their operations globally [START_REF] Brenkert | ISCT, hypernorms, and business: A reinterpretation[END_REF]. Twentieth-century French philosopher, Jacques Maritain, makes the distinction about how philosophers classify human beings in terms of understanding what constitutes people, and how they behave (1947/1962).

Persons are conceived in a Kantian or Descartes-ian sense in that they are treated as ends in themselves, and never as means to an end. This approach, however, discredits "the realistic and teleological notions of human nature" (Acevedo 2012: 199). We advocate a duality approach to the management of patent laws for intellectual property, which aligns an ethic of responsibility with both teleological and deontological decision criteria. We agree with Maritain to the extent he says that business ethics should be "a practical science that aims at procuring man's unqualified good…and the common good" (Maritain 1962: 196). The common good affirms the private good rather than precluding it. It is our hope that business ethicists and legal scholars alike will focus more heavily on the pragmatic portion of the intellectual property debate. In terms of digital technology, in particular, "it is especially critical to re-examine the underpinnings of the moral legitimacy for intellectual property protection" (Spinello 2003: 2).

Hans [START_REF] Jonas | Philosophical Essays: From Ancient Creed to Technological Man[END_REF][START_REF] Jonas | The Imperative of Responsibility: In Search of Ethics for the Technological Age[END_REF] calls for an imperative of responsibility to address modern problems associated with technological development and accelerated change. He notes that, "Science confers to man previously unknown forces, the economy constantly pushes forward in an unbridled impulse" (1984: 10). He emphasizes that straight deontological or teleological ethical theories are no longer sufficient for determining what is ethically desirable conduct.

Instead we must take a perspective of responsibility for the long-term effects of our decisions within interpersonal relationships and beyond. The ethics of responsibility suggests an imperative to human existence: to lead a life that is worthy of being called 'human'. Jonas calls for "a uniform theory of being" which rejects the dualistic ontology that dominates moral philosophies (1984: xxiii). This notion of an ethics based in responsibility can be linked to Emmanuel Levinas' work (1981Levinas' work ( /2006)). He called for a realignment for business ethics, one rooted in a responsibility to be ethical. "Levinasian moral philosophy calls for a business ethics that is conceived not as a corporate commitment but as an individual practice of responsibility by the agents of management towards the Other…" (Bevan & Corvellec 2007: 208). In other words, being ethical requires a duty to others. This duty originates outside of the self and depends on humans' ability to develop ethical relationships. To Levinas, current approaches to ethics are insufficient for resolving business ethics problems.

Similarly, to Jonas, previous conceptions of ethics leave humans unprepared because the horizons of time and space are changing at an accelerated pace [START_REF] Bernstein | Rethinking responsibility[END_REF]. Since Jonas' motivation for focusing on an ethics of responsibility is due to the observed accelerated pace of technological development, we feel his arguments are particularly relevant to a discussion about patents for innovation. Jonas claims that ethics needs to be grounded in metaphysics by rite of the knowledge and power humans possess over each other and to future existence (1984). This implies a long-range perspective on survival. It is noted that the responsibility transforms over time due, in part, to the acceleration of technology, and by consequence, social change.

In our paper we posit that it is possible to overcome the inherent dualism between the two categories (deontological and teleological) of ethics theories by means of the concept of responsibility without a compulsory metaphysical grounding of this concept. As with other universal moral values (e.g., liberty or justice), responsibility can be shared as a global reference without mandating an a priori consensus concerning its form of philosophical or metaphysical grounding. "Traditionally, deontology and utilitarianism are seen as competing theories of ethics…" each proposing a greater value than the other for solving society's challenges (Brady & Dunn 1995: 386). Utilitarians believe in the supremacy of the ends sought in a decision over the means it took to make that decision [START_REF] Cody | Honest Government: An Ethics Guide for Public Service[END_REF]. Consequentialists approach ethics in terms of "the empirical consequences to society" (Lewin 2007: 443). Some ethicists see a heavy utilitarian bias in economic activities [START_REF] Etzioni | Normative-affective factors: Toward a new decision-making model[END_REF], and claim there should be a more useful and realistic approach to making ethical decisions in business and public policy [START_REF] Resnik | A pluralistic account of intellectual property[END_REF][START_REF] Phillips | Ethics and network organizations[END_REF]. By the same token, an ethical system that is based solely on the respect of human rights (we see this through the Fair Information Practices Principles in intellectual property discussions) can lead to a never-ending discourse about which conflicting rights should take precedence across varied situations. These discussions also often are confounded with too much subjective preference (Acevedo 2012: 210).

In this present paper we suggest there be reconciliation between a concern for universality of principles (i.e., a true focus on responsibility), and the common good. Only then can policy makers make informed best judgments for society when faced with real situations [START_REF] Melle | Responsibility and the crisis of technological civilization: A Husserlian meditation on Hans Jonas[END_REF]). As we have mentioned, the current patent system is out of balance. In dealing with this issue, it is crucial to balance incentives to initial innovators against incentives to followon innovators. Although the point deserves further study, experience suggests that this balance is currently weighted too much in favor of the initial innovator. The problem is likely to become increasingly serious in biotechnology and computer software, where the practical limit on claim breadth "seems to be only the imagination of the claim drafter" [START_REF] Barton | Intellectual property rights: Reforming the patent system[END_REF](Barton : 1934)). In other words, it provides excessive incentive to IP inventors by granting too much temporal protection for the actual creation. Benefits to society are largely overlooked in this case. However, focusing too much on an open access solution may stifle innovation. Currently, the length of time granted to patent protection is not functioning effectively, and the length of time policy makers are granting innovators has increased since the inception of the patent right [START_REF] Atkinson | Building the global innovation economy[END_REF]. This has led to the enclosure movement in intellectual property rights discussions. This is when "a lengthy proprietary right is assigned to an intellectual work or some other form of common property so that it becomes unavailable to the public" (Spinello 2003: 1).

Hypothetically, if this protection lasted indefinitely, society would not benefit in that fewer innovations are likely to take place. Individuals' decisions have consequences that often span a longer time frame and across a greater number of stakeholders. Jonas believes that reframing modern moral issues in terms of responsibility addresses the changing scope of decision-making. For Jonas, responsibility is not defined by a person's behavior and the consequences that are generated by that behavior, but by something that causes an appeal in the person (or group) with the power to make the decision [START_REF] Melle | Responsibility and the crisis of technological civilization: A Husserlian meditation on Hans Jonas[END_REF]. However, within his concept of responsibility, Jonas makes a clear distinction between formal and substantive responsibility. Formal responsibility involves being accountable for one's actions, in a descriptive sense. No value judgment is made. With substantive responsibility though, humans "are responsible for the caring or preservation of some object" (Bernstein 1994: 840). The implication is that people have causal power over the world through, in part, the technological tools they create, which have long-term consequences to humanity. This notion, in particular, is relevant to patent protection. In the next section, we discuss the ethics of responsibility across levels of analysis in order to identify the place of the intellectual property debate within this specific type of ethics.

Ethics of Responsibility and its Interacting Levels

The ethics of responsibility interacts at three levels. There is an over-arching normative level (which Jonas considers "macro") of responsibility. These are the ideal values and principles of responsibility that are supposed to guide all of society. This is the conception of responsibility that is most substantive and should have the broadest appeal to individuals. The next level involves the social mechanisms and institutions of responsibility that are often manifested in law.

These are structural and context-dependent descriptions of responsibility [START_REF] Borsen Hansen | Academic and social responsibility of scientists[END_REF].

Finally, there is individual responsibility "where the ethical principles are translated into responsible actions…" (73).

For an ethics of responsibility to be a sufficient guide for behavior in an increasingly technological age, there should be an implicit objective good that is served which motivates individuals to have a long-term concern for others. Jonas emphasizes a naturally induced affect toward responsibility. In other words, he suggests an a priori emotion that drives individuals toward other-regarding behavior-a notion originally attributed to Adam Smith (1759).

Additionally, there exists a very different type of responsibility ethics, one borne out of the social constructions of reality. A contractual responsibility is a type of ethics, "which is conditional a posteriori upon the fact and terms of the relationship actually entered into" (Jonas 1984: 95).

Both aspects of the responsibility share three interlinked characteristics critical to the utility of ethic-totality, continuity and future. "Totality" implies an applicability to a variety of contexts.

"Continuity" is meant to convey the concept reliably over time. And, "future" emphasizes the long-term focus of the responsibility. "Act so that the effects of your action are compatible with the permanence of genuine human life" (Jonas 1984: 111). What are the proper contours of intellectual property protection then? Next, building on our discussion here, we address the specific nature of the ethical foundations of patent law for the basis needed to introduce our integrated model of ethics and innovation.

patent-granting procedure. The U.S. Supreme Court has supported this utilitarian argument on numerous occasions. In Diamond v. Chakrabarty, the Court noted, "[t]he patent laws promote this progress [of science and the useful arts] by offering inventors exclusive rights for a limited period as an incentive for their inventiveness and research efforts." In Kewanee Oil Co. v. Bicron Corp., the Court observed that, "[t]he productive effort thereby fostered [by the Patent Act] will have a positive effect on society through the introduction of new products and processes of manufacture into the economy, and the emanations by way of increased employment and better lives for our citizens." Finally, in Aronson v. Quick Point Pencil Co., the Court noted that the purposes of the federal patent systems are: 1) to foster and reward invention, 2) to promote invention disclosure, which stimulates further innovation and allows the public to practice the invention once the patent expires; and 3) to assure that the public can freely use ideas in the public domain.

Given these two competing ethical foundations for patent law, it is evident that a broader, more encompassing ethical approach such as that presented by Jonas is warranted. In the next section, we bring in our final key factor-the time horizon-before applying our framework of ethic and innovation to patent processes.

The Time Factor

Having revealed in the preceding sections the ethical factor as a critical explanatory variable for the described patent/innovation-problem, we examine in this section the role that changes in the time dimension play in the genesis of our patent/innovation problem. The leading question is: Is the time gap between technological advancement and legislative process a hindrance for overall social progress, necessitating a response from policy makers? In order to answer this question we proceed in two steps, helping us structure the time dimension.

First, we retake and specify the traditional distinction between the "subjective" and "objective" dimension of reality. It is important to emphasize that subjectivity, linked to the character of human nature, is not limited to the existence within a single person, but is shared by a group of persons-for example, managers or policy makers (Banerjee 1965). A shared form of subjectivity is transformed from a personal kind ("pure" subjectivity) to an interpersonal kind, called "inter-subjectivity". This "inter-subjectivity" provides the basis for "objectivity" which is possible with individuals and the scientific reference for social and legal domains. For a better understanding of our paper, we use the term "objective dimension" for the designation of facts independent from human perception and decision. In the subjective dimension, however, there exists a nuance between a pure, personal subjectivity and inter-subjectivity, which is present in all social processes and organizations. These two dimensions are also present in the temporal component of society where the objective time dimension is observed in (short, middle, or longterm) the tendencies of organizations, and the subjective time dimension exists in the (short, middle or long-term) orientation of decision-makers which result from their perception of time itself (Authors 2013: 12).

In our case it is understandable that a scientifically observed long-term tendency of organizations and patents can be challenged by the short-term tendency of certain technological innovations and a short-term orientation of the decision makers of the same organizationeventually setting it up for a temporal paradox. So, this distinction between the subjective and objective dimensions of time is also quite useful for our purpose here, as it permits us to focus time-related decisions more precisely. On this basis one can distinguish between decisions focusing on tendencies (taking them into consideration or trying to influence them) and decisions focusing on orientations (taking them into consideration or trying to influence them). 1The second step of our time investigation concerns the time-related phenomenon of speed. Analysing this phenomenon, Hartmut Rosa describes three forms of social acceleration of reality and three processes that drive them as explanations for the process of time acceleration [START_REF] Rosa | Alienation and Acceleration, Toward a critical theory of late-modern temporality[END_REF]). The "first, most obvious, and most measurable" form of social acceleration is technological acceleration. This is defined as the "intentional speeding up of goal-directed processes of transport, communication and production" (Rosa 2010:16). To support this contention, it should be noted that the speed of communication has increased by 10 7 , the speed of personal transport by 10 2 , and the speed of data processing by 10 6 [START_REF] Geibler | Vom Tempo der Welt: Am Ende der Uhrzeit at 89[END_REF]. Clearly, the processes that create this technological acceleration are often related to patents. The second form of social acceleration relates to social change. These changes focus on the "acceleration of society itself" and are concerned with the "accelerated processes of social change that rendered social constellations and structures as well as patterns of actions and orientation unstable and ephemeral" (Rosa 2010:18). The third form of social acceleration is the acceleration of the pace of life. It is defined as the "speed and compression of actions and experiences in everyday life" (22). This leads to another interesting paradox as there exists an increasing scarcity of time in one's everyday life, despite the technological acceleration discussed earlier. Each of these forms of social acceleration reinforces each other in an acceleration cycle.

Rosa contends that there are three external accelerators behind the three aforementioned dimensions of social change-economic, structural, and cultural. The first and most obvious source of social acceleration in Western societies is the economic motor, capitalism. The circle of production, distribution, and consumption constantly accelerates and can be summarized in the simplistic concept of time=money. This economic motor is the driving factor behind technological acceleration as new technologies are largely affected by economic forces. Social change is driven by the structural motor-modern society's basic structural principle of functional differentiation. From this perspective, society is not segregated into hierarchical classes; rather it is structured along the lines of functional systems, such as politics, the economy, and law. The driving factor behind the acceleration of the pace of life is the cultural motor, in which the idea of a fulfilled life consists of, "realizing as many options as possible from the vast possibilities the world has to offer" (Rosa 2010: 30).

Opposing these processes of social acceleration and the motors that drive them exist several factors that act to decelerate the aforementioned acceleration of time, resulting in "desynchronization". The most important entity in terms of the present discussion is political institutions. Rosa notes that, "these institutions historically played a key role in enabling social acceleration by providing stable and calculable background conditions, but are now in danger of being eroded by the very forces of acceleration they set in motion." (Rosa 2009: 102) Additionally, the process of functional differentiation has resulted in a number of subsystems, such as law and the economy that follow their own "temporal rhythms, patterns, and horizons" (104). This results in a tendency for political institutions to shift the decision-making process toward faster arenas, such as the legal system, the economy, or individual responsibility.

It becomes obvious that our patent/innovation problem is, according to Rosa, also due to a phenomenon of de-synchronization of technological speed and democratic legislation speed.

The complex set of reasons for the genesis of this phenomenon has been briefly explained above.

In our paper, the de-synchronization is combined with a temporal gap between the length of the innovation cycle of new technologies and the current duration of patents. This temporal gap often leads to a failure of patent law to achieve the duality of ethic and innovation. Given Rosa's de-synchronization concept, an alignment between patent duration and the technological time horizon would benefit both managerial innovation and society as a whole.

The duration of patent protection is the most direct way legislators have of controlling the scope of rights granted to innovators (Leveque & Meneiere 2004: 25). Furthermore, an economic analysis of patent duration provides a key argument in favor of limiting patent duration, as "it is preferable to forgo the creation of the most costly innovations in order to expand consumer access to less costly innovation" (29). In addition to benefiting consumers on the whole, a reduction of the patent term to a period of five to seven years would eliminate a significant portion of the patent threat faced by entrepreneurs and companies [START_REF] Kinsella | Reducing the cost of IP law[END_REF]. The costs borne by companies would be drastically reduced with fewer lawsuits real or threatened, lower insurance premiums, and reduced patent license fees and royalties.

We have shown in this paper that the concern of Jonas' ethics of responsibility focuses on the long-term survival of mankind and can provide a foundation for a moral system called: ethic of (long-term) responsibility.

Ethical Innovation for Patent Law Figure 1: Duality of Ethic and Innovation (from Authors 2013) HERE

In Figure 1, we present the typology along two dimensions: "Outcomes", and "Mechanisms".

Along both axes, the typology is split on Ethic and Innovation, highlighting the components of our Integrated Causal Model. Here we present the typology in the context of patent law and patent strategies.

Ethic is defined differently by axis. On the "Outcomes" axis, Ethic is thought of in terms of realized objectives, The other decision criterion that defines the behaviors in our typology relates to the "Mechanisms" of Ethic and Innovation. Ethic on this axis is defined at a macrolevel by the legal system and social norms. These are often manifested in institutions via mechanisms such as company values statements and mission statements.

On the other side of the same axis, innovation is presented. Given an accelerating business and economic environment, innovation processes are evaluated in terms of achieved adaptability, flexibility and creativity. The "Mechanisms" for Innovation involve organizational processes for creating and adapting. Here is where we see the temporal paradox identified earlier. Shorter-term solutions for patent laws enable a longer-term vision for innovations. How this is achieved is discussed on this axis. Figure 1 also illustrates the mutual interdependence of ethic and innovation-the duality (as seen in Quadrants II and III), as well as the other extreme, when one or the other is ignored, the organization is likely to face obstacles to survival (as seen in Quadrants I and IV). Next we briefly discuss the resulting behaviors within the typology.

In Quadrant I we predict the outcome when there is no attention given to new innovations, but the process does indeed include an ethic. Here there is risk of the moral system becoming overly rigid and inflexible; that the sustainability of the moral system is seriously in danger of breaking down. This would cause a "fossilized ethic". When the ethical norms are too strict so as to inhibit adaptability, innovation is stifled. For fear that the mechanisms controlling the moral norms going to be compromised, innovation is sacrificed. The patent law is overly restrictive to enable new innovations in order to protect the intellectual property rights of individuals or organizations. This causes organizations to employ a "fossilizing ethic" strategy.

We reiterate that innovation is critical for the ethic to be realized in the long-term.

More specifically, overly strict applications of patent laws often inhibit new innovations.

Yahoo utilized a "fossilized ethic" strategy when it chose to file a patent infringement suit against Facebook, just as the company was preparing to file its IPO [START_REF] Swisher | So it's the Kodak strategy for Yahoo -the last refuge of the vaguely patented[END_REF]. Former employees claimed that Yahoo was "weaponizing" patents they had created with the initial assurance that the patents were being created only as a precautionary measure to defend against companies who might sue Yahoo [START_REF] Baio | A patent lie: How Yahoo weaponized my work[END_REF]. Critics noted that Yahoo had pursued this offensive strategy in 2004 against Google before it went public, and that the actions signified a company, "bereft of talent to win any other way" [START_REF] Swisher | So it's the Kodak strategy for Yahoo -the last refuge of the vaguely patented[END_REF]. This approach also presents lost opportunity costs, as resources are taken away from innovation and instead poured into patent litigation [START_REF] Quinn | Yahoo and Facebook settle patent battle with strategic partnership[END_REF].

Quadrant II illustrates that decision makers perceive innovation as long-term oriented.

This orientation also assists with company survival and maintenance of its ethical code/norms. If decision makers are inclined to value innovation, then an "innovated ethic" could result.

Externally driven change is limited in the field of ethics by moderate innovation. As a result, the existing moral norms are likely to collapse or deteriorate. Self-organized, temporary structures and processes are designed by individuals and organizations in order to promote survival.

Creativity, new ideas, diversity, and cooperation are required elements of innovation. The collective interests of an organization must incorporate the long-term time dimension as well as other-regarding values. An inclination to understand the importance of addressing the needs of an organization's stakeholders through innovation is characteristic of an individual who has a survival ethic. Thus, an underlying ethic for the organization is enabled through the long-term vision of the decision-maker, which we contend should involve the ethic of responsibility.

An example of a Quadrant II approach can be found Ericsson's patent strategy. Rather than hoard patents with the intent of inhibiting market entrants via infringement suits, the Swedish-based global firm's approach is to allow others to use the patents on "fair, reasonable, and non-discriminatory" (FRAND) terms that ensure all can afford to use the solutions in their own products [START_REF] Brismark | Patent strategies -a fork in the road toward 4G[END_REF]. This is accomplished by choosing to charge a FRAND licensing fee to those wishing to utilize one of Ericsson's patents, as opposed to filing a patent infringement suit. As two of their Intellectual Property Officers note:

The communications industry should heed the dangers of being fragmented and stick to doing business in open competition within a framework set by all participants. The key to this is for each patent owner to follow the fairness principle; in other words, the question of reasonable total royalty and proportionality (Brismark & Alfalahi 2008: 65).

Working with patents in an open and collaborative manner is crucial to the future of the telecommunications industry, and consequently, society as a whole [START_REF] Brismark | Patent strategies -a fork in the road toward 4G[END_REF].

The outlook taken here is clearly one of a long-term perspective incorporating "other-regarding" values that maximizes community welfare while respecting individual patent rights. Thus, we see an ethic of responsibility toward others.

In the next cell, Quadrant III, we see a combination of an innovation-outcome orientation and an ethic mechanism. We see this as reflecting organizations that utilize ethics processes to facilitate long-term innovation. By rite of these firms' ethical awareness, survival goals are more easily realized. In other words, a vision for the long-term ethics of responsibility legitimizes the firm's innovation objectives. This quadrant is referred to as, "Ethical innovation." An example in our context follows.

In response to the actions taken by Yahoo's "fossilizing ethic" strategy, Twitter decided to follow an "ethical innovation" strategy and create the Innovators Patent Agreement (IPA) for its employees in regard to patents they created. The IPA has two key components: first, if an employee creates and assigns its patent to Twitter, the company will not use it to sue anyone unless the company is sued first; secondly, if the patent is sold to a different party, it can still only be utilized as the inventor intended [START_REF] Mchugh | Twitter announces new patent strategy: trolls need not apply[END_REF]. This novel approach to patent creation appeals to engineers who value "innovation over patents" and "want to see their inventions have an impact on people's lives" [START_REF] Raustiala | The Twitter I.P.O[END_REF]. The concern for others falls within the norm of the ethics of responsibility. The IPA approach represents a significant shift in the usual relationship between employees and employers, in which all decision-making rights are usually given to the employer regarding patents created by the employee [START_REF] Schultz | Twitter has a savvy new patent strategy[END_REF]. The result is an approach where an awareness of the ethical perspective of patent-creating employees is taken into account in order to effectuate long-term innovation. Thus, the social exchange in this instance is governed by an ethics of responsibility norm that enables innovation.

Finally, Quadrant IV reflects the opposite behavior found in the first quadrant. Here we see innovation taking place but with no regard to the ethics of responsibility, or any long-term, other-regarding concern. Rather, the innovations promoted by the organization are short-term in nature, usually with an immediate economic motive. Short-term profits serve as the motivation for decision-makers to act in a manner ignorant of ethical norms. For example, LeMenestral and Van Wasserhove (2004) describe an innovative operating model in the banking industry that was utilized to aid bankers achieve greater short-term profits by manipulating customers' service fees without their immediate knowledge. This decision, while innovative, violates customers' rights and demonstrates a lack of ethics. We consider this, "Unethical innovation."

An example of the principles inherent in "unethical innovation" can be found in the some of the recent actions of Goldman Sachs. The company generated large revenues during the subprime mortgage crisis through the use of financial instruments such as the credit default swap (CDS). CDSs are one of the most complex products used by investment banks, and are similar to a form of insurance that allows one to bet that an entity will default on some type of obligation. [START_REF] Tanner | Wall Street and patents: Financial innovation or ethical dilemma[END_REF]. Goldman Sachs filed aggressively for numerous financial instrument patents in the CDS area [START_REF] Tanner | Wall Street and patents: Financial innovation or ethical dilemma[END_REF]. CDSs are "a way to increase the leverage in the system, and the people who were doing it knew that they were doing something on the edge of fraudulent...They were not well motivated." [START_REF] Morgenson | Quoting Martin Meyer, It's time for swaps to lose their swagger[END_REF]). It appears as though Goldman Sachs either ignored the principles contained in their own CDS patent applications or found these principles inconvenient to exercise, with their judgment being blinded by the enormous profits from their CDSs [START_REF] Tanner | Wall Street and patents: Financial innovation or ethical dilemma[END_REF]. The history of CDS markets and attempts to regulate them show that clever risk management tools can and will often become extremely lucrative but also potentially risky financial instruments in the hands of financial "innovators" [START_REF] Koszeg | The evolution of credit default swaps and efforts to regulate them: What will be the impact of JP Morgan Chase's recent $2 billion trading loss?[END_REF]. As one commentator noted: Innovation in the area of finance -often lionized as crucial to rendering markets more efficient and hence as a key driver of social wealth -is actually subject to ethical criticism, or at least caution. And the worry is not just that particular innovations in this area have been problematic. The worry is that the pace of innovation has made it hard for regulators, investors, and ratings agencies to keep up (MacDonald 2011).

Goldman Sachs actions with CDS patents epitomize the unethical innovation described in Quadrant IV. Next we discuss the potential implications for future work in this area.

Implications

It can be established that the processes by which patents are granted are being driven by economic motors and are increasing the process of time acceleration. Furthermore, the political institutions which craft the patent laws are slowing down acceleration due to the inherent qualities found in the process for creating those laws. As a result, these institutions are pushing the decision-making aspects of patent law to more nimble actors, such as the U.S. court system.

But the courts lack the authority to make significant changes to patent law from a temporal perspective. By analyzing this problem with the aforementioned general concepts and theories, we do not pretend to offer generalized solutions for all types of innovation, for all types of organizations and for all types of countries in the world (in terms of economic development).

Rather, we limit our investigation in this present paper to current patent law challenges of global companies in the United States and to innovations with a short-term life cycle common to the technology sector.

Additionally, there exists a disconnect between the ethical foundations of patent law that we propose and the current norms of patent law processes. Both utilitarianism and the deontological approach are being utilized to support patent law systems in capitalist societies.

Given these two disparate foundations, there exists the managerial discretion for agents to design the social and economic exchanges in the prior section. However, under both of these analyses, the concept of "common good' from a societal perspective is being given short shrift. Too much emphasis is being placed upon the incentive provided to the creator in order to elicit the patentable creation. To remedy this, we are proposing a foundation based on the ethic of responsibility. One component of this newly proposed approach would be the reduction of patent terms under U.S. patent law. Such a change, based upon the ethic of responsibility, would more effectively realize the goal of serving the "common good," and successfully respond to the arguments presented in this paper. However, to what extent managers other countries and in other industries with innovations with other life cycles could learn from our research, should be examined in future research.

Thus, both 1) the "de-synchronisation" between the pace of technological development and the pace of patent law development and, 2) the change of meaning given to the ethical value of utility, have culminated in a patent duration that is disconnected from both its subject matter and its ethical moorings. The result is an improper temporal duration for which patent protection should exist, given the rapid rate of the technological acceleration of time and the ethical standards we propose for patent law systems. We hope this paper enhances the intellectual property dialogue about current patent law. We believe our duality approach to ethic and innovation centered around a long-term ethic of responsibility may be a potential normative solution to the problems with the current patent law process. An additional contribution is that we offer a usable, workable the ethical foundation of patent law. By utilizing the ethic of responsibility company approaches toward patent policy can be properly evaluated within broader contexts. While in this present research we focus on a particular business/legal context, we envision this standard being pragmatically useful for decision makers with a going concern.

Finally, future research on the ethics of responsibility should continue to look for a pragmatic operationalization which, on one hand, does not imply a compulsory philosophical or metaphysical grounding of responsibility, and which, on the other hand, allows the integration of the three levels of our presented concept of ethics. For the authors of this present piece, the Integrative Social Contract Theory (ISCT) of [START_REF] Donaldson | Ties That Bind[END_REF] represents such a promising operationalization approach. It is considered "the most powerful conceptual framework for both normative theorizing and positive empirical research at the intersection of business, management, and ethics and law" (Van Oosterhout & Heugens 2009: 729). It is possible to utilize the ethics of responsibility as a hypernorm which governs both micro and macro social contracts and would be adaptable over time. [START_REF] Brenkert | ISCT, hypernorms, and business: A reinterpretation[END_REF] recognizes the need for universal standards that supercede all local arrangements in contracting, but laments that ISCT does not consistently do this across varying contexts. In short, a moral justification of hypernorms could be addressed with the ethics of responsibility. This suggestion would not be limited to a patent law application opening up many future avenues of work.

This distinction of the two time dimensions is also inherent to the ICM-model, which will be explained in the next section.

Ethical Foundations of Patent Law

As discussed earlier, there are two primary foundations proffered to explain the ethical basis of patent law. The first of these is deontological and focuses on individual rights. The perspective taken here is that these particular property rights should be granted because of the labor invested by the creator on the front-end of the process. Noted patent expert, Donald Chisum, states that one theory supporting patent law is a natural rights justification under which, "the patent law protects the rights of inventors, regardless of the repercussions on public welfare" [START_REF] Chisum | Principles of Patent Law[END_REF]. Indeed, it is posited that the sole reason for the existence of government is to protect these natural rights, and the legal rights that provide this protection are based upon the preceding moral rights [START_REF] Resnik | A pluralistic account of intellectual property[END_REF]. Restrictions on these natural rights are not justified as a means of promoting social goals like utility or just distribution of resources. [START_REF] Nozick | Anarchy, State, and Utopia[END_REF]. Related to this view: A company's (or for that matter anyone's) moral right to the fruits of its discovery is independent of and antecedent to patent law. On the Lockean argument that people are entitled to the fruits of their labor, patent law simply recognizes and gives legal effect to the company's prior moral claims…If the law failed to guarantee the company's rights to the fruits of its discovery, then the law would be morally at fault (Maitland 2002: 464).

Thus, patent laws, as a form of property rights, are designed to protect individual interests relating to the investment of their labor [START_REF] Resnik | A pluralistic account of intellectual property[END_REF].

The other ethical foundation of patent law is utilitarian in nature, which takes the position of promoting the overall greatest good. Contrary to the deontological approach, this perspective is based on looking at the back-end of the process, toward what the consequences are of the


Ph.D Janitza L Montalvo-Ortiz

Ph.D Hang Zhou

Ph.D Ivana D'andrea

Ph.D Luc Maroteaux

Ph.D Adriana Lori

Ph.D Alicia Smith

M.D Kerry J Ressler

Yaira Z Nuñez

Ph.D Lindsay A Farrer

Ph.D Hongyu Zhao

M.D Henry R Kranzler

M.D Joel Gelernter
email: joel.gelernter@yale.edu

Translational studies support a role for serotonin 2B receptors in aggression-related cannabis response

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3,269 African-Americans (AAs) and 2,546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating a mouse Htr2b -/- knockout with THC resulted in increased aggressive behavior in the resident-intruder paradigm, while the opposite effect was observed in wild type mice following THC administration, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.

Introduction

Violent behavior is a major public health problem, resulting annually in approximately 1.43 million deaths worldwide [START_REF] Siever | Neurobiology of aggression and violence[END_REF] . Genetic factors explain 50-63% of the variance [START_REF] Schoeler | Continuity of cannabis use and violent offending over the life course[END_REF][START_REF] Veroude | Genetics of aggressive behavior: An overview. American journal of medical genetics[END_REF] ; several studies have identified genetic variants that influence aggressive behavior. Monoaminergic genes -identified via unbiased approaches or selected as biological candidates -have been extensively studied in relation to aggression-related traits [START_REF] Veroude | Genetics of aggressive behavior: An overview. American journal of medical genetics[END_REF][START_REF] Waltes | The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms. American journal of medical genetics[END_REF] . An apparently unique mutation at the monoamine oxidase A locus (MAOA), which encodes an enzyme that catabolizes monoamines (including serotonin), was associated with aggressive behavior in a Dutch kindred [START_REF] Brunner | Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A[END_REF] after first being localized by genetic linkage analysis [START_REF] Brunner | X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism[END_REF] . Caspi et al. [START_REF] Caspi | Role of genotype in the cycle of violence in maltreated children[END_REF] subsequently reported that carriers of a different low-activity MAOA variant exhibited violent behavior only after exposure to moderate or severe levels of child abuse [START_REF] Weder | MAOA genotype, maltreatment, and aggressive behavior: the changing impact of genotype at varying levels of trauma[END_REF] . Sequencing of serotonin-system genes in a Finnish population of impulsive individuals revealed association between a stop codon in the serotonin 2B receptor gene (HTR2B Q20*) and risk of committing violent acts [START_REF] Bevilacqua | A population-specific HTR2B stop codon predisposes to severe impulsivity[END_REF] . In a subsequent study, HTR2B Q20* carriers showed aggressive behavior, alcohol-related impulsivity, and emotional dysregulation [START_REF] Tikkanen | Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon[END_REF] .

Aggressive behavior is influenced by a combination of genetic and environmental factors, including substance use. A high proportion of all crimes are committed under the influence of substances of abuse [START_REF] Karberg | Substance Dependence, Abuse, and Treatment of Jail Inmates[END_REF] , and thus aggression while intoxicated is an important subtype of all aggressive behavior. Cannabis, one of the most widely used drugs worldwide, has been linked to increased impulsivity [START_REF] Solowij | Reflection impulsivity in adolescent cannabis users: a comparison with alcohol-using and non-substance-using adolescents[END_REF] and decreased behavioral inhibition [START_REF] Gruber | Age of onset of marijuana use impacts inhibitory processing[END_REF][START_REF] Bhattacharyya | Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis[END_REF] . The relationship between cannabis use and aggression has been established [START_REF] Schoeler | Continuity of cannabis use and violent offending over the life course[END_REF][START_REF] Renard | Long-term consequences of adolescent cannabinoid exposure in adult psychopathology[END_REF][START_REF] Barthelemy | Prenatal, perinatal, and adolescent exposure to marijuana: Relationships with aggressive behavior[END_REF][START_REF] Dugre | Persistency of Cannabis Use Predicts Violence following Acute Psychiatric Discharge[END_REF] ; cannabis use is associated with a 7-fold risk of subsequent violent and aggressive behavior [START_REF] Schoeler | Continuity of cannabis use and violent offending over the life course[END_REF] . A recent study of 1,136 subjects from the McArthur Risk Assessment study also found that continuity of cannabis use is associated with increased risk of future violent behavior (OR=2.44) [START_REF] Dugre | Persistency of Cannabis Use Predicts Violence following Acute Psychiatric Discharge[END_REF] .

We first conducted a genome-wide association study (GWAS) of physical aggression occurring under the influence of cannabis in African Americans (AA) and European Americans (EA) and a polygenic risk score (PRS) analysis to determine whether genetic risk factors for personality traits could predict cannabis-related aggression in humans. The GWAS implicated the serotonin 2B receptor gene (HTR2B), which was not previously considered a key cannabis target. We then evaluated the cannabis/Htr2b interaction in a mouse knockout model.

Methods

Subjects and Diagnostic Procedures Discovery cohort

Our GWAS discovery sample included 2,185 AA and 1,362 EA subjects selected from the Yale-Penn sample, all of whom endorsed having used cannabis 10 or more times. The initial sample (Yale-Penn 1) consisted of small nuclear families and unrelated individuals recruited at five US clinical sites: Yale University School of Medicine (APT Foundation, New Haven, CT), the University of Connecticut Health Center (Farmington, CT), the University of Pennsylvania, Philadelphia, PA), the Medical University of South Carolina (Charleston, SC) and McLean Hospital (Belmont, MA). Subjects were recruited for studies of the genetics of drug (opioid or cocaine) or alcohol dependence [START_REF] Gelernter | Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways[END_REF][START_REF] Gelernter | Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene[END_REF][START_REF] Gelernter | Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans[END_REF][START_REF] Gelernter | Genome-wide association study of alcohol dependence:significant findings in African-and European-Americans including novel risk loci[END_REF] . All subjects provided written informed consent as approved by the institutional review boards at each site, and certificates of confidentiality were obtained from NIDA and NIAAA. Subjects were interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), which yield reliable DSM-IV and DSM-5 criteria and diagnoses. Cannabis-related aggression (CRA) was assessed with the question, "Did you ever get into physical fights while using marijuana?" Results from the Yale-Penn 1 sample were combined via meta-analysis with results from 1,084 AA and 1,184 EA cannabis-exposed subjects who were identically ascertained (Yale-Penn 2 sample). The study cohorts are described in Table 1.

Replication cohort: Grady Trauma Project (GTP)

The subjects for this study were part of a larger investigation of genetic and environmental factors that predict response to stressful life events in a predominantly African American, urban population of low socioeconomic status [START_REF] Gillespie | Trauma exposure and stress-related disorders in inner city primary care patients[END_REF] . All subjects endorsed lifetime prevalence of cannabis use, assessed using the Structured Clinical Interview for the DSM-IV (SCID) [START_REF] First | Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I Research Version 2.0)[END_REF] . Aggressive behavior was assessed using the "Beat some up" item from the Aggressive Behavior Questionnaire (ABQ), a 48-item, self-report inventory of physical and verbal aggression, and criminal offenses including drug use and theft. This scale is based on the Conflict Tactics Scale, a commonly used measurement of relationship conflict behaviors [START_REF] Straus | A short form of the Revised Conflict Tactics Scales, and typologies for severity and mutuality[END_REF] . The aggression measure was examined as a quantitative trait among these cannabis-exposed subjects.

Genotyping and Quality Control Discovery cohort

The Yale-Penn samples were genotyped using one of two genotyping arrays: 1) for the Yale-Penn 1 sample, the Illumina HumanOmni1-Quad v1.0 microarray was used (988,306 autosomal SNPs; Illumina, San Diego, CA, USA) at the Center for Inherited Research (CIDR) and the Yale Center for Genome Analysis (YCGA) and 2) for the Yale-Penn 2 sample, the Illumina Infinium Human Core Exome microarray (265,919 exomefocused SNPs and 243,345 tagging SNPs which allow genome-wide imputation) at our lab. All QC and subsequent analyses were performed separately within individuals genotyped on the two platforms. Genotypes were called using GenomeStudio software V2011.1 and genotyping module V1.8.4 (Illumina, San Diego, CA, USA). SNPs with significantly different allele frequencies (within population) across genotyping centers were set to missing prior to imputation. SNPs were filtered by minor allele frequency (MAF) < 0.01 and imputation score threshold of 0.8. After imputation, data cleaning, and QC, in AAs 15,101,332 SNPs and in EAs 8,365,931 SNPs were successfully metaanalyzed.

To verify and correct the misclassification of self-reported race, we compared the GWAS data from all subjects with the genotypes from the HapMap 3 reference CEU, YRI and CHB, and 1000 Genomes reference AFR, EUR, and ASN populations. Principle components (PC) analysis was conducted in the merged sample using Eigensoft [START_REF] Price | Principal components analysis corrects for stratification in genome-wide association studies[END_REF][START_REF] Patterson | Population structure and eigenanalysis[END_REF] . The first 10 PCs were used to remove outliers and to distinguish AAs and EAs; these groups were subsequently analyzed separately. We then conducted PC analyses within the two remaining groups as previously described [START_REF] Sherva | Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks[END_REF] , and the first three PCs were used in all subsequent analyses to correct for residual population stratification.

Grady Trauma Project (GTP) sample:

Quality control was performed using the Psychiatric Genomics Consortium PTSD Workgroup guidelines. Additional details are provided in Supplementary Notes.

Statistical Analysis Methods

Association tests were performed using logistic regression models embedded in generalized estimating equations (GEE) to correct for correlations among related individuals [START_REF] Zeger | Longitudinal data analysis for discrete and continuous outcomes[END_REF] . We modeled CRA as a binary variable, analyzed in a standard logistic regression and adjusted for age, sex, and three PCs of ancestry. Analyses were conducted separately within each population group, corrected for the genomic-inflation factor (λ) and combined by meta-analysis using the inverse variance method in the program METAL [START_REF] Willer | METAL: fast and efficient meta-analysis of genomewide association scans[END_REF] . Conditional analysis was conducted to determine whether closely mapped genome-wide significant (GWS) SNPs represent independent signals. We conducted statistical testing as previously described, using a logistic regression model embedded in GEE with age, sex, three PCs, and the SNP of interest as covariates.

For the GTP cohort, we also conducted a logistic regression analysis to determine the association between rs17440378 and aggression-related trait in AA subjects with a lifetime prevalence of cannabis. The aggression-related trait used was "Beat someone up", and modeled as a continuous variable (Never=0, Once=1, Sometime=2, Many times=3, More than I can count=4) with age, sex, and first 3 PCs as covariates.

We used publicly available bioinformatics tools to identify the functional effects of the GWS variants found in our CRA GWAS. Additional details are provided in Supplementary Notes.

Polygenic risk score analysis

To test for pleiotropy between the NEO personality factors and CRA, we conducted a PRS analysis using GWAS data from the five-factor model traits of neuroticism, extraversion, openness, agreeableness and conscientiousness, measured with the NEO Personality Inventory (NEO PI-R) [START_REF] Costa | Stability and change in personality assessment: the revised NEO Personality Inventory in the year 2000[END_REF] . The public summary data were downloaded from the website of the Genetics of Personality Consortium (GPC, http://www.tweelingenregister.org/GPC/). Additional details are provided in Supplementary Notes.

Htr2b knockout mice, THC administration and behavioral phenotyping

A total of 34 mice (20 wild type, 14 Htr2b -/-knockout) of 129SvPas background were used in the study; wild type (WT) mice were used as a control group. Saline or THC (10 mg/kg) was administered by intraperitoneal (i.p.) injection, 1 hour before test. The selected THC dose was based on a previous study showing that THC (10 mg/kg) decreases social interaction in mice [START_REF] Long | Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence[END_REF] . Behavioral test, and animal care were conducted in accordance with the standard ethical guidelines (National Institutes of Health's 'Guide for the care and use of laboratory animals', and European Directive 2010/63/UE). All experiments involving mice were approved by the local ethical committee (N°1170.02). Aggressive behavior was investigated using the resident-intruder test adapted from Koolhaas and colleagues [START_REF] Koolhaas | The residentintruder paradigm: a standardized test for aggression, violence and social stress[END_REF] and performed 1 hour after i.p. injection. Additional details are provided in Supplementary Notes.

Behavioral data were analyzed using two-way ANOVA with genotype (knockout vs. WT) and treatment (saline vs. THC) as between-subjects factors. Tukey's test was used for post hoc comparisons with significance set at p < 0.05. Analyses were carried-out using GraphPad Prism 6 (GraphPad Software Inc., La Jolla, CA, USA).

Results

We studied two samples, Yale-Penn 1 and Yale-Penn 2 [START_REF] Sherva | Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks[END_REF] . In Yale-Penn 1, the prevalence of cannabis-related aggression (CRA) was 13.9% in AAs and 10.8% in EAs, while in Yale-Penn 2 it was 13.1% in AAs and 8.4% in EAs (Table 1). GWAS results are summarized in Manhattan plots (Supplementary Figure 1), Table 2 and Supplementary Tables 1 and2. Quantile-Quantile plots are shown in Supplementary Figures 2 and3.

GWAS of cannabis-related aggression identified a GWS locus at HTR2B/PSMD1.

We identified one genome-wide significant (GWS) region on chromosome 2 in AAs (Regional Manhattan plot, Figure 1). The top SNPs included rs35750632 (β=0.54, P=1.79×10 -8 ) in the proteasome 26S subunit, non-ATPase 1 gene (PSMD1) and rs17440378 (β=0.57, P=2.16×10 -8 ) in HTR2B. The coding region of HTR2B is contained within that of PSMD1 (Figure 1); the lead variants are ~43 kb apart and in high LD (r 2 = 0.42, D'= 0.98). Conditional analysis confirmed that both SNPs reflect the same association signal. A There was no GWS SNPs in EAs. In AAs only, there was a dose-dependent relationship between CRA and HTR2B*rs17440378 genotype (Supplementary Figure 4), with TT genotype (MAF=0.1) associated with higher CRA: CC (n=2587), CRA=12.1%; CT (n=640), CRA=18.9%; TT (n=42), CRA=28.6%. Genome-wide meta-analysis of AA and EA samples showed no additional GWS SNPs. P-values of association, effect size, and effect direction of HTR2B*rs17440378 for CRA are shown in Figure 2 (upper panel). Annotation analysis was conducted using publicly available bioinformatics tools (Braineac, GTEx, and HaploReg v4.1) to identify the functional effects of the GWS variants found in the CRA GWAS. We found that HTR2B*rs17440378 is an eQTL for HTR2B and nearby genes (PSMD1, C2orf72, DIS3L2, SP140, B3GNT7) across several brain regions, (e.g., medulla, substantia nigra, and putamen) and peripheral tissue (Supplementary Tables 3 and4; Supplementary Figures 567). Multiple epigenetic marks were also identified for HTR2B*rs17440378 (Supplementary Tables 5 and6), suggesting a functional regulatory role for this GWS SNP.

Grady Trauma Project (GTP) sample: A total of 89 AA subjects with data available for cannabis and aggression had previously been genotyped using the Illumina Omni-Quad 1M Array [START_REF] Powers | A genome-wide association study of emotion dysregulation: Evidence for interleukin 2 receptor alpha[END_REF] ; the HTR2B*rs17440378 variant was imputed (r 2 =0.99). HTR2B*rs17440378 show a significant association (p=0.04, one sided) with aggression in subjects with a lifetime prevalence of cannabis, with an effect size similar to that in the discovery sample (Table 2).

Polygenic risk score analysis for CRA and NEO factors.

Using P-value thresholds of 0.001 and 0.005, polygenic risk scores (PRS) of extraversion were significantly associated with CRA, with the most significant result obtained for the SNP set (n=6,772) with a P-value threshold of 0.001 (Figure 4; Supplementary Table 7). Extraversion PRS predicted greater CRA risk (p=5.70x10 -3 , b=0.67, S.E.=0.24).

THC increases aggressive behavior in Htr2b -/-mice. Htr2b -/-mice exhibited more impulsive behaviors and greater novelty-induced locomotion than wildtype (WT) mice [START_REF] Bevilacqua | A population-specific HTR2B stop codon predisposes to severe impulsivity[END_REF] . In the present study, Htr2b -/-mice were abnormally aggressive (p<0.001 vs. WT), as shown by the significant effect of genotype on Aggressive Behavior (Fs (1,30) = 413.6 and 118.7, respectively for frequency and duration, P < 0.0001 for both) and had less social interaction (p<0.001 vs. WT) in the resident-intruder paradigm (Figure 4). A significant effect of treatment x genotype interaction for both Aggressive Behavior (Fs (1,30) = 21.25 and 17.26, respectively for frequency and duration, P < 0.0001 and P =0.0002) and Social Investigation (Fs (1,30) = 7.553 and 6.017, respectively for frequency and duration, P < 0.0001 for both) suggested a different response to THC treatment on the two genotype groups. Indeed, acute THC treatment (10 mg/kg, i.p.) induced an opposite effect on aggressive response by genotype: post-hoc comparisons showed increased aggression in Htr2b -/-mice (p<0.05 vs. Htr2b -/-saline control) and reduced aggression in WT mice (p<0.01 vs. WT saline control) (Figure 4A andB). Further, THC significantly increased the propensity to social investigation only in WT mice (p<0.05 vs. WT saline control; Figure 4C andD), but not in in Htr2b -/-mice. Htr2b -/-mice were also hyperactive, as shown by the statistically significant effect of treatment x genotype interaction for crossing frequency (F (1,30) = 16.55, P = 0.0003; Supplementary Figure 8). In particular, post-hoc analysis revealed that saline Htr2b -/- mice crossed more the cage surface compared saline WT mice (p < 0.001). Furthermore, THC treatment decreased locomotion in both WT and Htr2b -/-mice (respectively, p <0.01 and p <0.001 vs. each respective saline control) (Supplementary Figure 8).

Discussion

In this first GWAS of CRA, we report GWS evidence linking HTR2B to cannabis response. We identified one GWS region mapped to HTR2B, which overlaps PSMD1. Functional analysis revealed genomic regulatory roles for HTR2B*rs17440378, mainly in brain tissue. HTR2B*rs17440378 also showed nominally significant association in the GTP sample with a related (but non-identical) phenotype. This specific locus is one of the best supported in previous studies of aggression phenotypes (that unlike the present study, used a candidate-locus approach) 9,10 and the serotonin system is very well established as being related to traits involving violence and impulsivity. However, although serotonergic function is strongly implicated in cannabis response [START_REF] Muller | The role of serotonin in drug use and addiction[END_REF] , we are aware of no prior evidence implicating this particular receptor. PRS analysis showed that extraversion was significantly associated with CRA; higher extraversion predicted greater risk for CRA. Further, Htr2b -/-mice that received THC exhibited a greater aggressive response than WT mice, with the latter showing a reduced aggressive response, suggesting that Htr2b modulates aggression-related cannabis response.

Aggressive behavior is influenced by both genetic and environmental factors, including substance use. Cannabis use is associated with greater impulsive decision making [START_REF] Solowij | Reflection impulsivity in adolescent cannabis users: a comparison with alcohol-using and non-substance-using adolescents[END_REF] and less behavioral inhibition [START_REF] Bhattacharyya | Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis[END_REF] , critical contributors to risk-taking, substance use, and aggressive behavior. Cannabis use and cannabis withdrawal also contribute to aggression and related traits [START_REF] Smith | Marijuana withdrawal and aggression among a representative sample of U.S. marijuana users[END_REF] ; cannabis use is associated with increased subsequent violent behavior [START_REF] Schoeler | Continuity of cannabis use and violent offending over the life course[END_REF][START_REF] Dugre | Persistency of Cannabis Use Predicts Violence following Acute Psychiatric Discharge[END_REF] . The identification of genetic factors contributing to the risk for aggressive behavior following cannabis use provides opportunities both for prevention and treatment.

Our CRA GWAS identified GWS loci at and near HTR2B. It is noteworthy that this GWAS, by nature hypothesis-free, landed on this gene, as it has previously been closely associated with impulsivity and aggressive behaviors in both humans and animal models. A stop codon variant of HTR2B (HTR2B Q20*) was associated to impulsivity in Finns [START_REF] Bevilacqua | A population-specific HTR2B stop codon predisposes to severe impulsivity[END_REF] . A follow-up functional annotation analysis of rs17440378, the HTR2B intronic polymorphism, provided the best evidence of functionality based on its numerous regulatory effects in brain and peripheral tissues. HTR2B*rs17440378 is an eQTL for HTR2B and nearby genes. Multiple regulatory epigenetic marks were identified for rs17440378 in brain and peripheral tissue, including anterior caudate, involved in reward and cognitive function [START_REF] Hikosaka | Basal ganglia circuits for reward value-guided behavior[END_REF] , and cingulate gyrus, implicated in schizophrenia [START_REF] Bersani | Cingulate Cortex in Schizophrenia: its relation with negative symptoms and psychotic onset. A review study[END_REF] and threat processing in humans [START_REF] Fiddick | There is more than the amygdala: potential threat assessment in the cingulate cortex[END_REF] . Based both on its demonstrated contribution to aggressive behavior and our functional annotation analysis, HTR2B appears to be the relevant gene rather than PSMD1.

The risk effect of HTR2B*rs17440378 appeared to be specific to individuals who are aggressive under the influence of cannabis, rather than being driven by drug dependence alone, aggression alone, or aggression referable to drugs other than cannabis (Figure 2). Decreased or null expression of HTR2B has been linked to impulsivity [START_REF] Bevilacqua | A population-specific HTR2B stop codon predisposes to severe impulsivity[END_REF][START_REF] Tikkanen | Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon[END_REF] , schizophrenia-like behaviors [START_REF] Pitychoutis | Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype[END_REF] , impaired social interaction [START_REF] Pitychoutis | Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype[END_REF] , and resistance to selective serotonin reuptake inhibitor antidepressants [START_REF] Diaz | Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants[END_REF] . We extended these findings by showing that Htr2b -/-mice exhibit greater aggressive behavior and decreased social interaction than WT mice in the resident-intruder test. HTR2B variation may therefore interact with cannabis use to induce aggression by reducing brain monoaminergic tone. Interestingly, null expression or blockade of 5-HT 2B receptors diminishes the reinforcing effects of psychoactive drugs by modulating serotonin [START_REF] Doly | Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice[END_REF] and dopamine [START_REF] Doly | Serotonin 2B receptors in mesoaccumbens dopamine pathway regulate cocaine responses[END_REF] signaling. In this study, we found that THC induces opposite effects in aggressive behavior and social interaction by Htr2b status: THC increased aggression and no change in social investigation in Htr2b -/- mice, while it decreased aggression and increased social investigation in WT mice.

Personality traits may contribute to the comorbidity of psychiatry disorders, so we conducted a PRS analysis to determine the genetic overlap of CRA and personality traits. Our results indicated that PRS for extraversion were associated with CRA, with higher Extraversion also shows high genetic correlation with bipolar disorder and attention deficit hyperactivity disorder (ADHD). Further, extraversion is positively associated with externalizing behavior [START_REF] Muris | Self-reported reactive and regulative temperament in early adolescence: relations to internalizing and externalizing problem behavior and "Big Three" personality factors[END_REF] , and it has been linked to excitement-and attention-seeking behavior, as well as social and interpersonal dysfunction [START_REF] Trull | Dimensional models of personality: the five-factor model and the DSM-5[END_REF] .

Our human study is limited by the sample size, especially among EAs. Significant results were observed in AAs only, an effect that may be population-specific. Although the association is not statistically significant in EAs, the effect direction is the same; the meta-analysis of both populations yielded a p-value of 3.06 × 10 -7 , i.e., it reduced significance. Thus, the effect may also be present in EAs, but a larger sample is needed to evaluate this possibility. Larger samples with additional phenotypic information would also be required to assess additional relevant possibly-correlated or confounding factors such as testosterone levels, psychosocial environment, and socio-economic status. In addition, human genomic and precision medicine research is limited by a lack of racial diversity, with 96% of GWAS participants reportedly being of European descent [START_REF] Need | Next generation disparities in human genomics: concerns and remedies[END_REF] . This limited our ability to identify an AA cohort of adequate size with the phenotypic assessment necessary to replicate our findings. However, we found a significant association of HTR2B*rs17440378 and aggression in AA subjects with a history of cannabis use. The lack of direct assessment of the effects of HTR2B*rs17440378 on protein function, including regulation, is a limitation of our study; however, eQTL analysis helped us to understand the functionality of this risk variant in genomic regulation of HTR2B and nearby genes in peripheral and brain tissue. Further, there is clear biological relevance of the GWS locus, HTR2B, a gene previously shown to play an important role in aggression and impulsivity traits. The prior evidence for this gene and the findings from the animal model further support the role of this gene in CRA.

Our findings support a role of 5-HT 2B receptors in the modulation of the aggression-related cannabis response, identify a specific mechanism that could result in violence in the context of cannabis use, and provide the first evidence that this is an important site for cannabis response. Medications acting at 5-HT 2B receptors may be relevant in modifying such behaviors acutely. For example, an 5-HT 2B receptor antagonist, such as the widely used antipsychotic aripiprazole, may, based on the evidence presented herein, exacerbate cannabis-related aggression, an interesting idea given its effects on the response to the acute administration of methamphetamine [START_REF] Stoops | Influence of aripiprazole pretreatment on the reinforcing effects of methamphetamine in humans[END_REF] and in the treatment of depression [START_REF] Chen | Second-generation antipsychotics in major depressive disorder: update and clinical perspective[END_REF] , schizophrenia [START_REF] Fleischhacker | A doubleblind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia[END_REF] , and agitation in autism [START_REF] Owen | Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder[END_REF] . This plot shows the genome-wide significant association between cannabis-related aggression and a single nucleotide polymorphism (SNP) rs17440378 (purple) at the HTR2B locus. Each circle represents a SNP, the left y-axis reflects the -log 10 (P value), and the light blue line and right axis the observed recombination rate. Color coding (dark blue, blue, green, yellow, and red) shows the degree of linkage disequilibrium (r 2 ) between rs17440378 (purple, diamond shaped) and other SNPs in the region. Centimorgan (cM), megabase (Mb).

Figure 1 .

 1 Figure 1. Association results for cannabis-related aggression (CRA) in African Americans. Regional association plot of 231.8-to 232.1-MB region on chromosome 2 encompassing HTR2B and PSMD1 in the Yale-Penn African-American participants after meta-analysis.This plot shows the genome-wide significant association between cannabis-related aggression and a single nucleotide polymorphism (SNP) rs17440378 (purple) at the HTR2B locus. Each circle represents a SNP, the left y-axis reflects the -log 10 (P value), and the light blue line and right axis the observed recombination rate. Color coding (dark blue, blue, green, yellow, and red) shows the degree of linkage disequilibrium (r 2 ) between rs17440378 (purple, diamond shaped) and other SNPs in the region. Centimorgan (cM), megabase (Mb).

Figure 2 .

 2 Figure 2. Forest plot of rs17440378 (chr2:231979355), a genome-wide significant SNP for cannabis-related aggression (CRA). The blue lines represent 95% confidence intervals of the effect size estimates. The blue rectangles are proportional to the square-root of the sample size. The blue diamonds represent the meta-analysis estimate of AAs and EAs. Abbreviations: Cannabis related aggression (CRA), cannabis dependence (CaD), alcohol dependence (AD), cocaine dependence (CocD), opioid dependence (OD), antisocial personality disorder (ASPD), conduct disorder (CD), alcohol-related aggression (ARA), cocaine-related aggression (CocRA), opioid-related aggression (ORA).

Figure 3 .

 3 Figure 3. Results of polygenic risk score analyses predicting cannabis-related aggression (CRA) based on polygenic risk scores from NEO personality factors. Polygenic risk scores (PRS) were calculated using P-value thresholds of 0.00001 -0.5. (A) We show the PRS of P-value threshold of 0.0001 for agreeableness, and 0.001 for conscientiousness, openness, extraversion, and neuroticism. Extraversion polygenic risk scores were significantly positively associated with CRA (p = 5.70 × 10 -3 , b= 0.67, S.E. = 0.24). Error bars represent data ± standard error (S.E.).

Figure 4 .

 4 Figure 4. THC increases aggressive behavior in Htr2b -/-mice. Effects of acute THC treatment (10 mg/kg, i.p.) on aggressive behavior and social interaction in Htr2b -/-and WT (Htr2b +/+ ) mice. (A-B) Htr2b -/-mice showed more aggressive behavior than WT. THC treatment significantly increased the aggressive response in Htr2b -/-mice; an opposite and significant effect was observed in WT mice. (C-D) THC treatment reduced social investigation in Htr2b -/-mice. Genotype effect: *** and * = P < 0.001 and 0.05, respectively. Treatment effect: ** and * = P < 0.01 and 0.05, respectively. Error bars represent data ± standard error (S.E.).

Table 1 . Demographic characteristics of the study cohorts.

 1 Abbreviations: SD, standard deviation; CRA, cannabis-related aggression; CaD, cannabis dependence; AD, alcohol dependence; CocD, cocaine dependence; OD, opioid dependence; ASPD, antisocial personality disorder; CD, conduct disorder; N/A, not applicable.

		Yale-Penn 1		Yale-Penn 2		GTP
		African	European	African	European	African
		American	American	American	American	American
	Characteristic	(n=2185)	(n=1362)	(n=1084)	(n=1184)	(n=89)
	Age, mean (SD), y	41.2 (8.4)	36.8 (10.4)	40.6 (10.6)	37.5 (12.2)	45.0 (10.7)
	Female sex, No. (%)	852 (39.0)	501 (36.8)	331 (30.5)	374 (31.6)	44 (49.4)
	CRA, n (%)	304 (13.9)	147 (10.8)	142 (13.1)	99 (8.4)	N/A
	CaD, n (%)	895 (49.4)	566 (55.2)	503 (55.6)	506 (61.3)	N/A
	AD, n (%)	1322 (71.2)	865 (82.2)	741 (80.4)	787 (87.7)	N/A
	CocD, n (%)	1892 (87.6)	1070 (82.1)	675 (64.3)	621 (61.1)	N/A
	OD, n (%)	637 (29.8)	868 (65.9)	295 (27.7)	573 (55.2)	N/A
	Age of onset cannabis use, mean (SD), y	15 (4.6)	14 (3.7)	15 (5.6)	14 (2.8)	N/A
	More than 1 before 15, n (%)	945 (43.3)	720 (52.9)	438 (40.4)	527 (48.6)	N/A
	Years exposed to cannabis, mean (SD), y	21 (13.0)	15 (11.7)	19 (13.1)	14 (12.8)	N/A
	Frequency cannabis use (>100), n (%)	1969 (90.1)	1259 (57.6)	970 (44.4)	930 (42.6)
	Aggression (physical fights), n (%)	1362 (62.6)	791 (58.2)	702 (64.8)	611 (56.4)	N/A
	Sober Aggression (physical fights), n (%)	322 (14.7)	78 (5.7)	201 (18.5)	65 (6.0)	N/A
	ASPD, n (%)	340 (15.9)	232 (17.4)	207 (19.6)	213 (19.9)	N/A
	CD, n (%)	56 (2.6)	49 (3.7)	29 (2.7)	33 (3.1)	N/A

Acknowledgments

We appreciate the work in recruitment and assessment provided at Yale University School of Medicine and the APT Foundation by James Poling, Ph.D.; at McLean Hospital by Roger Weiss, M.D., at the Medical University of South Carolina by Kathleen Brady, M.D., Ph.D., and Raymond Anton, M.D.; and at the University of Pennsylvania by David Oslin, M.D. We are grateful to Ann Marie Lacobelle and Christa Robinson for their excellent technical assistance, to the SSADDA interviewers who devoted substantial time and effort to phenotype the study sample, and to John Farrell and Alexan Mardigan for database management assistance. Assistance with data cleaning was provided by the National Center for Biotechnology Information. This study was supported by National Institutes of Health grants RC2 DA028909, R01 DA12690, R01 DA12849, R01

MH14276 and the NARSAD Young Investigator Grant to JLMO. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). Although unrelated to the current study, HRK has been a consultant, advisory board member, or CME speaker for Indivior and Lundbeck. He is also a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which in the last three years was supported by Abbvie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, and Xenoport. LM and ID'A have been supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de