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Confirmation of prior evidence of genetic susceptibility to alcoholism in a genome-wide association study of comorbid alcoholism and bipolar disorder

Lydall, Gregory Johna; Bass, Nicholas J.a; McQuillin, Andrewa; Lawrence, Jacoba; Anjorin, Adebayoa; Kandaswamy, Radhikaa; Pereira, Anaa; Guerrini, Irenea; Curtis, Davidb; Vine, Anna E.b; Sklar, Pamelac,d,e,f; Purcell, Shaun M.c,d,e,f; Gurling, Hugh Malcolm Douglasa

doi: 10.1097/YPG.0b013e32834915c2
Original Articles

Objectives: Alcoholism and affective disorders are both strongly comorbid and heritable. We have investigated the genetic comorbidity between bipolar affective disorder and alcoholism.

Methods: A genome-wide allelic association study of 506 patients from the University College London bipolar disorder case–control sample and 510 ancestrally matched supernormal controls. One hundred forty-three of the bipolar patients fulfilled the Research Diagnostic Criteria diagnosis of alcoholism. A total of 372 193 single nucleotide polymorphisms (SNPs) were genotyped. Genes previously shown to be associated with alcoholism and addiction phenotypes were then tested for association in the bipolar alcoholic sample using gene-wise permutation tests of all SNPs genotyped within a 50-kb region flanking each gene.

Results: Several central nervous system genes showed significant (P<0.05) gene-wise evidence of association with bipolar alcoholism. The genes implicated, which replicated genes previously shown to be associated with alcoholism were: cadherin 11, collagen type 11 α2, neuromedin U receptor 2, exportin7, and semaphorin-associated protein 5A. The SNPs most strongly implicated in bipolar alcoholism, but, which did not meet conventional genome-wide significance criteria were the insulin-like growth factor-binding protein 7, carboxypeptidase O, cerebellin 2, and the cadherin 12 genes.

Conclusion: We have confirmed the role of some genes previously shown to be associated with alcoholism in the comorbid bipolar alcoholism subgroup. In this subgroup, bipolar disorder may lower the threshold for the phenotypic expression of these alcoholism susceptibility genes. We also show that some genes may independently increase susceptibility to affective disorder and alcoholism.

aDepartment of Mental Health Sciences, University College London, Molecular Psychiatry Laboratory

bCentre for Psychiatry, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK

cCenter for Human Genetic Research

dDepartment of Psychiatry, Massachusetts General Hospital

eDepartments of Genetics, Psychiatry, or Medicine, Harvard Medical School, Boston

fBroad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

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Correspondence to Dr Hugh Malcolm Douglas Gurling, MBBCh, MRCPsych, Research Department of Mental Health Sciences, Molecular Psychiatry Laboratory, Windeyer Institute for Medical Science, University College Medical School, University College London, London W1T 4JF, UK Tel: +44 207 679 9474; fax: +44 207 679 9437; e-mail: h.gurling@ucl.ac.uk

Received July 12, 2010

Accepted May 8, 2011

© 2011 Lippincott Williams & Wilkins, Inc.