Genome-wide Linkage Scan of Antisocial Behavior, Depression and Impulsive Substance Use in the UCSF Family Alcoholism Study

Epidemiological (e.g., Grant and Harford, 1995; Grant et al., 2004; Kessler et al., 1997; Regier et al., 1990; Stinson et al., 2005) and clinical studies (e.g., Babor et al., 1992; Cloninger, 1987b; Hesselbrock et al., 1985; Morey and Blashfield, 1981; Ross et al., 1988) suggest that rates of depression, antisocial personality disorder, and illicit substance use are elevated among individuals diagnosed with alcohol dependence relative to individuals without this diagnosis. Given these high rates of co-occurrence, samples selected for alcohol dependence can be expected to be enriched for depression, antisocial behavior, and other substance use disorders. Further, each of these associated phenotypes show substantial genetic influences in their etiology as demonstrated by numerous twin studies (depression - Cadoret et al., 1985; Kendler et al., 1994, antisocial behavior - Lyons et al., 1995; Slutske et al., 1997, substance misuse - Kendler et al., 2003a; Tsuang et al., 1996). Thus, it is reasonable to utilize populations selected for alcohol dependence to identify genetic loci that contribute to the development of depression, antisocial behavior, and substance use phenotypes. Such an approach is not without risks, however. Twin studies suggest that a shared genetic etiology is, in part, responsible for the phenotypic correlation between antisocial behavior and alcohol dependence (Hicks et al., 2004; Kendler et al., 2003b). Similarly, shared genetic influences have been reported to underlie the phenotypic correlations between mood and anxiety disorders and alcohol dependence (Kendler et al., 1993; Khan et al., 2005; Wender et al., 1986), and shared genetic influences have also been reported to underlie the phenotypic correlations between illicit substance use and alcohol dependence (Han et al., 1999; Young et al., 2006). Although such studies suggest that significant overlap exists in the genetic risk associated with these phenotypes, they also demonstrate that unique genetic influences contribute to their development. As a result, studies investigating the genetic contributions to these phenotypes must be careful to evaluate the extent to which linked genomic loci are due to the unique genetic etiologies of each phenotype and the extent to which they are the result of a shared genetic etiology. The present study builds upon our previous efforts using scales from the Minnesota Multiphasic Personality Inventory - 2nd edition (MMPI-2; Butcher et al., 1989) to identify genetic influences that contribute to the development of depressive symptoms, antisocial behavior, and substance misuse (Gizer et al., 2010) and alcohol dependence (Gizer et al., 2011) in the University of California at San Francisco Family Alcoholism Study (SFFAM). Results from the former study suggested that the Depression (DEP), Antisocial Practices (ASP), and MacAndrew Alcoholism-Revised (MAC-R) scales from the MMPI-2 yielded quantitative measures of depression, antisocial behavior, and impulsive substance use, respectively, that were elevated among individuals diagnosed with alcohol dependence relative to those without the diagnosis in the SFFAM. Further, each scale showed evidence of familial transmission suggesting their utility in molecular genetic studies. The ASP scale of the MMPI-2 was designed to assess antisocial attitudes and behaviors associated with psychopathy (Butcher et al., 1990), and has shown moderate correlations with similar measures (Lilienfeld, 1996). The DEP scale is primarily composed of items assessing an individual's feelings of inadequacy and low self-worth (Butcher et al., 1990). It has shown moderate correlations with other depression measures such as the Beck Depression Inventory (Ben-Porath et al., 1993; Boone, 1994). The MAC-R scale was originally constructed to differentiate alcoholic outpatients from outpatients with other psychiatric conditions (MacAndrew, 1965). Subsequent research has demonstrated that the MAC-R assesses general substance misuse rather than alcoholism specifically and may be more accurately interpreted as a measure of impulsive drug use and reward seeking (Allen, 1991; Greene and Garvin, 1988; MacAndrew, 1979). Reward seeking behavior, which refers to an array of approach and consumption behaviors, is influenced by dopamine neurons in the mesolimbic pathway, which includes the nucleus accumbens and ventral tegmental area (Ikemoto and Panksepp, 1999). Several drugs including cocaine and methamphetamine directly stimulate this pathway, though research has shown that activities such as eating, sexual behavior, and even aggression can stimulate this pathway as well (Berridge, 2004). Thus, high reward-seeking behavior has been related to substance use disorders and antisocial behavior, which are thought to result from dysregulation of the mesolimbic pathway (Cloninger, 1987a). To further explore the conclusion that the ASP, DEP, and MAC-R scales may represent useful phenotypes for molecular genetic studies of antisocial behavior, depression, and impulsive substance use, respectively, we conducted genome-wide linkage scans for each of these scales in the present study. Because the SFFAM sample was selected for alcohol dependence and previous studies of the SFFAM have also shown high rates of cannabis use among the participants (Ehlers et al., 2010a; Ehlers et al., 2010b; Vieten et al., 2004), a second set of linkage scans using alcohol and then cannabis dependence diagnoses as covariates were conducted to determine the extent to which genetic loci identified in the initial analyses were unique or shared with the etiology of alcohol or cannabis dependence. The results of these analyses and the implications of these findings for future molecular genetic studies of substance dependence are discussed.