Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism Danielle M. Dick, 1,8 Kevin Jones, 2 Nancy Saccone, 1 Anthony Hinrichs, 1 Jen C. Wang, 1 Alison Goate, 1 Laura Bierut, 1 Laura Almasy, 3 Marc Schuckit, 4 Victor Hesselbrock, 5 Jay Tischfield, 6 Tatiana Foroud, 7 Howard Edenberg, 7 Bernice Porjesz, 2 and Henri Begleiter 2 Received 27 Jan. 2005—Final 15 July 2005 The use of endophenotypes has been proposed as a strategy to aid gene identification efforts for complex phenotypes [Gottesman, I. I., and Shields J. (1972). Schizophrenia and Genetics: A Twin Study Vantage Point. London: Academic]. As part of the Collaborative Study of the Genetics of Alcoholism (COGA) project, we have analyzed electrophysiological endopheno- types, in addition to clinical diagnoses, as part of our effort to identify genes involved in the predisposition to alcohol dependence. In this paper we summarize published results from linkage and association analyses of two chromosomal regions in which the use of endophenotypes has successfully led to the identification of genes associated with alcohol dependence [GABRA2 (Edenberg et al., (2004). Am. J. Hum. Genet. 74:705714) and CHRM2 (Wang et al., (2004). Hum. Mol. Genet. 13:19031911)]. Our experience in the COGA project has been that the analysis of endophenotypes provides several advantages over diagnostic phenotypes, including the strength and localization of the linkage signal. Our results provide an illustration of the successful use of endophenotypes to identify genes involved in the predisposition to a complex psychiatric phenotype, a strategy originally proposed by Gottesman and Shields in 1972. KEY WORDS: Alcohol dependence; association; EEG; endophenotype; genetics; linkage. INTRODUCTION Identifying genes involved in complex human behaviors and clinical disorders has proven difficult. Early enthusiasm (Egeland et al., 1987; Gershon et al., 1988) was quickly curtailed (Kelsoe et al., 1989), as it became apparent that the strategy suc- cessfully employed to identify genes for many single- gene disorders would not be nearly as useful for identifying most of the genetic variation contributing to complex phenotypes. Many strategies have been adopted in gene identification efforts to deal with the complexities introduced by studying disorders that are believed to have multifactorial, polygenic origins, rather than simple Mendelian patterns of inheritance. One strategy that has been proposed is the use of endophenotypes. Psychiatric diagnoses were formulated for the purpose of clinical classification and communication between care providers. Diagnoses are based on observable symptoms and there is considerable 1 Washington University School of Medicine, St. Louis, MO USA. 2 State University of New York, New York, NY USA. 3 Southwest Foundation for Biomedical Research, San Antonio, TX USA. 4 University of California, San Diego, CA USA. 5 University of Connecticut Health Center, Farmington, CT USA. 6 Rutgers University, New Brunswick, NJ USA. 7 Indiana University School of Medicine, Indianapolis, IN USA. 8 To whom correspondence should be addressed at Department of Psychiatry, Washington University in St. Louis, Box 8134, 660 South Euclid Ave., St. Louis, MO 63110, USA. Tel.: +1-314- 286-2297; Fax: +1-314-286-2213; e-mail: dickd@wustl.edu 112 0001-8244/06/0100-0112/0 Ó 2006 Springer Science+Business Media, Inc. Behavior Genetics, Vol. 36, No. 1, January 2006 (Ó 2006) DOI: 10.1007/s10519-005-9001-3