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Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism

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Abstract

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 endophenotypes, 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.

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Acknowledgments

The Collaborative Study on the Genetics of Alcoholism (COGA) (Principal Investigator: H. Begleiter; Co-Principal Investigators: L. Bierut, H. Edenberg, V. Hesselbrock, B. Porjesz) includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-Investigators are: University of Connecticut (V. Hesselbrock); Indiana University (H. Edenberg, J. Nurnberger Jr., P.M. Conneally, T. Foroud); University of Iowa (S. Kuperman, R. Crowe); SUNY HSCB (B. Porjesz, H. Begleiter); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice); University of California at San Diego (M. Schuckit); Howard University (R. Taylor); Rutgers University (J. Tischfield); Southwest Foundation (L. Almasy). Zhaoxia Ren serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA08401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). In memory of Theodore Reich, M.D., Co-Principal Investigator of COGA since its inception and one of the founders of modern psychiatric genetics, we acknowledge his immeasurable and fundamental scientific contributions to COGA and the field.

The first author DMD would also like to thank Dr. Irving Gottesman for comments on an earlier draft of this manuscript, and more generally, for his invaluable mentorship.

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Authors and Affiliations

  1. Washington University School of Medicine, St. Louis, MO, USA

    Danielle M. Dick, Nancy Saccone, Anthony Hinrichs, Jen C. Wang, Alison Goate & Laura Bierut

  2. State University of New York, New York, NY, USA

    Kevin Jones, Bernice Porjesz & Henri Begleiter

  3. Southwest Foundation for Biomedical Research, San Antonio, TX, USA

    Laura Almasy

  4. University of California, San Diego, CA, USA

    Marc Schuckit

  5. University of Connecticut Health Center, Farmington, CT, USA

    Victor Hesselbrock

  6. Rutgers University, New Brunswick, NJ, USA

    Jay Tischfield

  7. Indiana University School of Medicine, Indianapolis, IN, USA

    Tatiana Foroud & Howard Edenberg

  8. Department of Psychiatry, Washington University in St. Louis, Box 8134, 660 South Euclid Ave., St. Louis, MO, 63110, USA

    Danielle M. Dick

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  1. Danielle M. Dick
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Correspondence to Danielle M. Dick.

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Dick, D.M., Jones, K., Saccone, N. et al. Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism. Behav Genet 36, 112–126 (2006). https://doi.org/10.1007/s10519-005-9001-3

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