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An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry

Abstract

Fast beta (20–28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10−8. The most significantly associated SNP, rs11720469 (β: −0.124; P<4.5 × 10−9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

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Acknowledgements

The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B Porjesz, V Hesselbrock, H Edenberg, L Bierut, includes 11 different centers: University of Connecticut (V Hesselbrock); Indiana University (HJ Edenberg, J Nurnberger Jr, T Foroud); University of Iowa (S Kuperman, J Kramer); SUNY Downstate (B Porjesz); Washington University in St Louis (L Bierut, J Rice, K Bucholz, A Agrawal); University of California at San Diego (M Schuckit); Rutgers University (J Tischfield, A Brooks); University of Texas Rio Grand Valley (L Almasy), Virginia Commonwealth University (D Dick), Icahn School of Medicine at Mount Sinai (A Goate), and Howard University (R Taylor). Other COGA collaborators include: L Bauer (University of Connecticut); J McClintick, L Wetherill, X Xuei, Y Liu, D. Lai, S O’Connor, M Plawecki, S Lourens (Indiana University); G Chan (University of Iowa; University of Connecticut); J Meyers, D Chorlian, C Kamarajan, A Pandey, J Zhang (SUNY Downstate); J-C Wang, M Kapoor, S Bertelsen (Icahn School of Medicine at Mount Sinai); A Anokhin, V McCutcheon, S Saccone (Washington University); J Salvatore, F Aliev, B Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grand Valley). A Parsian and M Reilly are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by an NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). JLM is supported by K01DA037914 from the National Institute on Drug Abuse (NIDA), JES acknowledges support from K01AA024152 (NIAAA) and AA acknowledges support from K02DA032573 (NIDA). Funding support for GWAS genotyping performed at the Johns Hopkins University Center for Inherited Disease Research was provided by the National Institute on Alcohol Abuse and Alcoholism, the NIH GEI (U01HG004438), and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). GWAS genotyping was also performed at the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine, which is partially supported by NCI Cancer Center Support Grant no. P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant no. UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.

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The authors declare no conflict of interest. However, unrelated to this work, AA (coauthor) received peer-reviewed funding, travel and an honorarium from ABMRF (end December 2012), which receives support from the brewing industry.

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Meyers, J., Zhang, J., Wang, J. et al. An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry. Mol Psychiatry 22, 1767–1775 (2017). https://doi.org/10.1038/mp.2016.239

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