Heritability of Fearful-Anxious Endophenotypes in Infant Rhesus Macaques: A Preliminary Report Douglas E. Williamson, Kris Coleman, Silviu-Alin Bacanu, Bernie J. Devlin, Jeffrey Rogers, Neal D. Ryan, and Judy L. Cameron Background: Research efforts to discover the genetic underpinnings of anxiety and depression is challenging because of the etiologic heterogeneity inherent to these disorders. These efforts might be aided by the study of related behavioral phenotypes in model organisms, such as monkeys. Methods: Eighty-five rhesus monkeys (Macaca mulatta) from the Oregon National Primate Research Center were drawn from a standard matriarchal colony and tested for behavioral response in four testing paradigms designed to elicit fearful-anxious reactions. Heritabilities were esti- mated using variance component-based quantitative ge- netic analyses with much of the genetic information arising from paternal half-sibs. Results: Individual behaviors reflecting increased distress responses (e.g., vocalizations and teeth grinding) and behavioral inhibition (e.g., latency to leave mother, la- tency to inspect novel fruit) showed significant heritability, even though a small number of monkeys were assessed. Exploratory factor analyses identified seven clusters of behaviors across tests, some of which were found to be heritable. Conclusions: These results indicate that several specific fearful-anxious behaviors in infant rhesus monkeys are heritable within this colony. Accordingly, these pheno- types, which are believed to represent the genetic liability for anxiety and depression, are good candidates for further genetic investigation in this population. Biol Psychiatry 2003;53:284 –291 © 2003 Society of Biologi- cal Psychiatry Key Words: Endophenotypes, heritability, model organ- isms, anxiety, depression Introduction A nxiety and depressive disorders are strongly familial, especially those beginning in childhood or early adulthood (Kovacs and Devlin 1998; Moldin et al 1991; Williamson et al 1995, 1999). The younger the age of the affected proband, the greater the hazard for the disorder in family members (Kupfer et al 1989; Neuman et al 1997; Weissman et al 1988; Williamson et al 1995), suggesting that early onset may represent a highly genetic form of the disease. Anxiety and depressive disorders are comorbid and co-occur within families (Angold and Costello 1993; Kovacs et al 1989; Ryan et al 1987; Williamson et al, 1999). As reviewed by Kovacs and Devlin (1998), adop- tion, twin, and family studies suggest that both kinds of illness have a genetic basis and that the same genes can affect liability to both kinds of disorders (e.g., Kendler et al 1987, 1992, 1993, 1995; Williamson et al 1999); however, despite the mounting evidence suggesting that these two common, intertwined psychiatric illnesses have a substantial genetic component, it could still be difficult to identify these genetic causes, as has proven true for similarly complex diseases (Risch 2000). Heterogeneity of the anxiety and depression phenotypes argues for careful consideration of designs for genetic analysis. One possibly efficacious strategy is to study traits that predate the onset of the disorders or are strongly associated with disease. Furthermore, these traits should be assessable in all family members regardless of the degree to which they are affected. Although not a panacea, such strategies have the potential to increase the power of the analysis (Blangero et al 2000). For early-onset anxiety and depression, such traits or “endophenotypes” could include putative biological markers such as growth hor- mone response to challenge, which has been shown to be blunted in depressed children (Dahl et al 2000), children at high risk for depression (Birmaher et al 2000), as well as adults with anxiety disorders (Price et al 1995; Uhde 1986). Another potentially fruitful approach involves studying behavioral traits that are believed to underlie the risk for developing anxiety or depression. For example, temperamental characteristics reflecting behavioral inhibi- From the Department of Psychiatry (DEW, KC, S-AB, BJD, NDR, JLC), Univer- sity of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania; Oregon National Primate Research Center (KC, JLC), Beaverton, Oregon; Southwest National Primate Research Center (JR), San Antonio, Texas. Address reprint requests to Douglas E. Williamson, Ph.D., Department of Psychi- atry, University of Pittsburgh School of Medicine, Room E-723, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh PA 15213. Received May 13, 2002; revised July 29, 2002; accepted August 1, 2002. © 2003 Society of Biological Psychiatry 0006-3223/03/$30.00 PII S0006-3223(03)01601-3