Common genetic influences on depression, alcohol, and substance use disorders in Mexican‐American families

Hispanics are now the largest ethnic-minority group in the United States, making up 15% of the population with over 46 million people (www.census.gov). As with other racial/ethnic groups, the leading mental health diagnoses among individuals of Mexican origin born in the U.S. are depression and alcohol and/or other substance use disorders (Alegria et al., 2008). Relatively little is known about potential differences in the pathophysiologic mechanisms of these mental illnesses in the Mexican-American population. Improving our understanding of the genetic and environmental factors that increase risk for mood and substance use disorders in this underserved ethnic minority could lead to better clinical care for Mexican-Americans. Despite clinical and etiological heterogeneity, there is increasing evidence that liability for major depressive disorder and liability for alcohol/substance use disorders is under genetic control. Numerous studies document the heritability of major depressive disorder at roughly 0.40 (Kendler et al., 2006; Kendler et al., 2001; Kendler et al., 1993). Similarly, the heritability of alcohol use disorders ranges from 0.40–0.60 (Goldman et al., 2005; Grant et al., 2009; Kendler et al., 1997) and the heritability for illicit drug use disorders is 0.30–0.80 (Goldman et al., 2005; Kendler et al. 2006, Tsuang et al., 1996), suggesting similar levels of genetic influence on major depression and alcohol and drug disorders (Bienvenu et al., 2010). However, Hispanics have not been adequately represented in behavioral or molecular genetic studies of these common psychiatric illnesses (Oquendo et al., 2010). The under-representation of Mexican American individuals in these studies, and in the genetic repositories maintained by the National Institute of Mental Health and the National Institute on Drug Abuse, may reflect explicit attempts by investigators to minimize population stratification, or may be an unintended consequence of selecting symptomatically homogeneous samples, as ethnic groups like Hispanics may have subtle differences in clinical presentation (Kleinman 2004). In either case, one potential consequence of the under-representation of the largest ethnic minority in the United States in genetic studies of major depression and alcohol/substance use disorders is the inability to elucidate genetic and environmental vulnerabilities specific for this population. Lifetime comorbidity between drug and alcohol use disorders and major depression has been consistently observed in clinical and epidemiological samples (Grant and Harford 1995; Hasin et al., 2007; Kessler et al., 1997; Regier et al., 1990; Schuckit et al., 1997). This pattern of comorbidity may be at least partly attributable to shared genetic factors (Kendler et al., 2003; Prescott et al., 2000). While there is significant phenotypic heterogeneity in the expression of these disorders, it is possible that more clinically homogeneous subtypes, particularly those with more severe clinical course (multiple episodes and/or early onset), may have a higher genetic loading (Kendler et al., 1993; Kendler et al., 1999; Weissman et al., 1988) and therefore may be more amenable to gene discovery (Levinson 2006; Levinson et al., 2007). In this context, it is possible that identifying common genetic factors between alcohol and substance use disorders and major depression could reduce the heterogeneity of each phenotype, thereby improving the potential for determining the risk genes for these common mental illnesses. In this manuscript, we report on the prevalence and phenomenology of major depression and coexisting alcohol/substance use disorders, in a community-based, ascertained sample of Mexican-American families, consisting of 1,122 persons. Our goals are (1) to estimate the heritability of major depressive disorder, alcohol and drug use disorders in Mexican-American families and (2) to examine evidence for pleiotropy between substance disorders and depression. In addition, we examined clinical subtypes of major depression (e.g. recurrent major depression, early onset major depression, recurrent-early onset major depression), with the expectation that early onset and recurrence of major depression would be associated with relatively stronger genetic control than more broadly defined DSM-IV major depression (Levinson 2006; McGuffin et al., 1996; McGuffin et al., 2003).