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Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism

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Abstract

Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q < 0.05); and 19 and 6 SNPs, respectively, that were significantly associated with these two disorders after region-wide correction by SNPSpD (8.9 × 10−5 ≤ p  ≤ 0.0003 and 2.4 × 10−5 ≤ p ≤ 0.0003, respectively). No variants were significantly associated with the other nine neuropsychiatric disorders, including alcohol dependence. We concluded that common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans.

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Acknowledgments

We thank for Dr. Daniel Winstead’s helpful comments. This work was supported in part by National Institute on Drug Abuse (NIDA) Grants K01 DA029643 and R01DA016750, National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants R01 AA016015 and R21 AA020319 and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Award 17616 (L.Z.). We thank NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype and genotype data from his/her original study (e.g., Drs. Bierut, Edenberg, Heath, Singleton, Hardy, Foroud, Myers, Gejman, Faraone, Sonuga-Barke, Sullivan, Nurnberger, Devlin, Monaco, etc.), and the primary funding organization that supported the contributing study. Funding and other supports for phenotype and genotype data were provided through the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) (U01HG004422, U01HG004436 and U01HG004438); the GENEVA Coordinating Center (U01HG004446); the NIAAA (U10AA008401, R01AA013320, P60AA011998); the NIDA (R01DA013423); the National Cancer Institute (P01 CA089392); the Division of Neuroscience, the NIA National Institute of Neurological Disorders and Stroke (NINDS); the NINDS Human Genetics Resource Center DNA and Cell Line Repository; the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C); the Center for Inherited Disease Research (CIDR); a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention; the NIH Office of Research on Women’s Health (ORWH) (R01NS45012); the Department of Veterans Affairs; the University of Maryland General Clinical Research Center (M01RR165001), the National Center for Research Resources, NIH; the National Institute of Mental Health (K01MH086621, R01MH059160, R01MH59565, R01MH59566, R01MH59571, R01MH59586, R01MH59587, R01MH59588, R01MH60870, R01MH60879, R01MH61675, R01MH62873, R01MH081803, R01MH67257, R01MH81800, U01MH46276, U01MH46282, U01MH46289, U01MH46318, U01MH79469, U01MH79470 and R01MH67257); the NIMH Genetics Initiative for Bipolar Disorder; the Genetic Association Information Network (GAIN); the Genetic Consortium for Late Onset Alzheimer’s Disease; the Autism Genome Project, the MARC: Risk Mechanisms in Alcoholism and Comorbidity; the Molecular Genetics of Schizophrenia Collaboration; the Medical Research Council (G0601030) and the Wellcome Trust (075491/Z/04), University of Oxford; the Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717, NWO Genomics, SPI 56-464-1419) the Centre for Neurogenomics and Cognitive Research (CNCR-VU); Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR); and the European Union (EU/WLRT-2001-01254), ZonMW (geestkracht program, 10-000-1002). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Genetic Consortium for Late Onset Alzheimer’s Disease, the GENEVA Coordinating Center (U01 HG004446), and the National Center for Biotechnology Information. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research, and GlaxoSmithKline, R&D Limited. The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap. The dbGaP accession numbers include phs000125.v1.p1, phs000021.v3.p2, phs000021.v3.p2, phs000167.v1.p1, phs000167.v1.p1, phs000267.v1.p1, phs000016.v2.p2, phs000092.v1.p1, phs000092.v1.p1, phs000181.v1.p1, phs000020.v2.p1, phs000017.v3.p1, phs000017.v3.p1, phs000017.v3.p1, phs000168.v1.p1, phs000219.v1.p1, phs000101.v3.p1, phs000292.v1.p1, phs000292.v1.p1, phs000102.v1.p1, phs000196.v2.p1, phs000126.v1.p1, phs000089.v3.p2, phs000089.v3.p2, phs000089.v3.p2 and phs000089.v3.p2.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA

    Lingjun Zuo, John H. Krystal, Matthew State & Xingguang Luo

  2. Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA

    Kesheng Wang

  3. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA

    Xiang-Yang Zhang

  4. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    Xinghua Pan

  5. Yale Center for Genome Analysis, Yale University School of Medicine, Orange, CT, USA

    Guilin Wang

  6. Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China

    Yunlong Tan

  7. Department of Neurology, Renji Hospital, Shanghai Jiaotong University, Shanghai, China

    Chunlong Zhong

  8. Department of Biostatistics, Yale University School of Epidemiology and Public Health, New Haven, CT, USA

    Heping Zhang

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  1. Lingjun Zuo
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  10. Heping Zhang
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Correspondence to Lingjun Zuo or Xingguang Luo.

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Zuo, L., Wang, K., Zhang, XY. et al. Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism. Hum Genet 132, 735–743 (2013). https://doi.org/10.1007/s00439-013-1277-4

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