Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genome-wide meta-analysis of copy number variations with alcohol dependence

The Pharmacogenomics Journal volume 18, pages 398–405 (2018)Cite this article

Subjects

Abstract

Genetic association studies and meta-analyses of alcohol dependence (AD) have reported AD-associated single nucleotide polymorphisms (SNPs). These SNPs collectively account for a small portion of estimated heritability in AD. Recent genome-wide copy number variation (CNV) studies have identified CNVs associated with AD and substance dependence, suggesting that a portion of the missing heritability is explained by CNV. We applied PennCNV and QuantiSNP CNV calling algorithms to identify consensus CNVs in five AD cohorts of European and African origins. After rigorous quality control, genome-wide meta-analyses of CNVs were carried out in 3243 well-diagnosed AD cases and 2802 controls. We identified nine CNV regions, including a deletion in chromosome 5q21.3 with a suggestive association with AD (OR=2.15 (1.41–3.29) and P=3.8 × 10−4) and eight nominally significant CNV regions. All regions were replicated with consistent effect sizes across studies and populations. Pathway and gene–drug interaction enrichment analyses based on the resulting genes indicated the mitogen-activated protein kinase signaling pathway and the recombinant insulin and hyaluronidase drugs, which were relevant to AD biology or treatment. To our knowledge, this is the first genome-wide meta-analysis of CNVs with addiction. Further investigation of the AD-associated CNV regions will provide better understanding of the AD genetic mechanism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Gelernter J, Kranzler HR . Genetics of alcohol dependence. Hum Genet 2009; 126: 91–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gelernter J, Kranzler HR, Sherva R, Almasy L, Koesterer R, Smith AH et al. Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol Psychiatry 2014; 19: 41–49.

    Article  CAS  PubMed  Google Scholar 

  3. Frank J, Cichon S, Treutlein J, Ridinger M, Mattheisen M, Hoffmann P et al. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addict Biol 2012; 17: 171–180.

    Article  CAS  PubMed  Google Scholar 

  4. Li D, Zhao H, Gelernter J . Further clarification of the contribution of the ADH1C gene to vulnerability of alcoholism and selected liver diseases. Hum Genet 2012; 131: 1361–1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li D, Zhao H, Gelernter J . Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biol Psychiatry 2011; 70: 504–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li D, Zhao H, Gelernter J . Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet 2012; 131: 725–737.

    Article  CAS  PubMed  Google Scholar 

  7. Cao J, Hudziak JJ, Li D . Multi-cultural association of the serotonin transporter gene (SLC6A4) with substance use disorder. Neuropsychopharmacology 2013; 38: 1737–1747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cao J, LaRocque E, Li D . Associations of the 5-hydroxytryptamine (serotonin) receptor 1B gene (HTR1B) with alcohol, cocaine, and heroin abuse. Am J Med Genet B Neuropsychiatr Genet 2013; 162B: 169–176.

    Article  PubMed  Google Scholar 

  9. Cao J, Liu X, Han S, Zhang CK, Liu Z, Li D . Association of the HTR2A gene with alcohol and heroin abuse. Hum Genet 2014; 133: 357–365.

    Article  CAS  PubMed  Google Scholar 

  10. Li D, Sulovari A, Cheng C, Zhao H, Kranzler HR, Gelernter J . Association of gamma-aminobutyric acid A receptor alpha2 gene (GABRA2) with alcohol use disorder. Neuropsychopharmacology 2014; 39: 907–918.

    Article  CAS  PubMed  Google Scholar 

  11. Sulovari A, Kranzler HR, Farrer LA, Gelernter J, Li DW . Further analyses support the association between light eye color and alcohol dependence. Am J Med Genet B 2015; 168: 757–760.

    Article  Google Scholar 

  12. Sulovari A, Kranzler HR, Farrer LA, Gelernter J, Li DW . Eye color: a potential indicator of alcohol dependence risk in European Americans. Am J Med Genet B 2015; 168: 347–353.

    Article  CAS  Google Scholar 

  13. Palmer RH, McGeary JE, Francazio S, Raphael BJ, Lander AD, Heath AC et al. The genetics of alcohol dependence: advancing towards systems-based approaches. Drug Alcohol Depend 2012; 125: 179–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carter NP . Methods and strategies for analyzing copy number variation using DNA microarrays. Nat Genet 2007; 39: S16–S21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ulloa AE, Chen JY, Vergara VM, Calhoun V, Liu JY . Association between copy number variation losses and alcohol dependence across African American and European American ethnic groups. Alcohol Clin Exp Res 2014; 38: 1266–1274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin P, Hartz SM, Wang JC, Agrawal A, Zhang TX, McKenna N et al. Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence. Alcohol Clin Exp Res 2012; 36: 1512–1518.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Li D, Zhao H, Kranzler HR, Li MD, Jensen KP, Zayats T et al. Genome-wide association study of copy number variations (CNVs) with opioid dependence. Neuropsychopharmacology 2015; 40: 1016–1026.

    Article  CAS  PubMed  Google Scholar 

  18. Cabana-Dominguez J, Roncero C, Grau-Lopez L, Rodriguez-Cintas L, Barral C, Abad AC et al. A highly polymorphic copy number variant in the NSF gene is associated with cocaine dependence. Sci Rep 2016; 6: 31033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007; 17: 1665–1674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P et al. QuantiSNP: an objective Bayes Hidden-Markov model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res 2007; 35: 2013–2025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang J, Lee SH, Goddard ME, Visscher PM . GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 2011; 88: 76–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sulovari A, Li D . GACT: a genome build and allele definition conversion tool for SNP imputation and meta-analysis in genetic association studies. BMC Genomics 2014; 15: 610.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Biggerstaff BJ, Tweedie RL . Incorporating variability in estimates of heterogeneity in the random effects model in meta-analysis. Stat Med 1997; 16: 753–768.

    Article  CAS  PubMed  Google Scholar 

  26. Viechtbauer W . Conducting meta-analyses in R with the metafor package. J Stat Softw 2010; 36: 1–48.

    Article  Google Scholar 

  27. Wang J, Duncan D, Shi Z, Zhang B, WEB-based GEne SeT . AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res 2013; 41: W77–W83.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M . Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 2014; 42: D199–D205.

    Article  CAS  PubMed  Google Scholar 

  29. Sulovari A, Chen YH, Hudziak JJ, Li D . Atlas of human diseases influenced by genetic variants with extreme allele frequency differences. Hum Genet 2017; 136: 39–54.

    Article  PubMed  Google Scholar 

  30. Maglott D, Ostell J, Pruitt KD, Tatusova T . Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res 2011; 39: D52–57.

    Article  CAS  PubMed  Google Scholar 

  31. Hewett M, Oliver DE, Rubin DL, Easton KL, Stuart JM, Altman RB et al. PharmGKB: the pharmacogenetics knowledge base. Nucleic Acids Res 2002; 30: 163–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Benjamini Y, Hochberg Y . Controlling the false discovery rate - a practical and powerful approach to multiple testing. J Roy Stat Soc B Met 1995; 57: 289–300.

    Google Scholar 

  33. Thevenin A, Ein-Dor L, Ozery-Flato M, Shamir R . Functional gene groups are concentrated within chromosomes, among chromosomes and in the nuclear space of the human genome. Nucleic Acids Res 2014; 42: 9854–9861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sham PC, Purcell SM . Statistical power and significance testing in large-scale genetic studies. Nat Rev Genet 2014; 15: 335–346.

    Article  CAS  PubMed  Google Scholar 

  35. Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J et al. An integrated map of structural variation in 2,504 human genomes. Nature 2015; 526: 75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruderfer DM, Hamamsy T, Lek M, Karczewski KJ, Kavanagh D, Samocha KE et al. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat Genet 2016; 48: 1107–1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Joslyn G, Ravindranathan A, Brush G, Schuckit M, White RL . Human variation in alcohol response is influenced by variation in neuronal signaling genes. Alcohol Clin Exp Res 2010; 34: 800–812.

    Article  CAS  PubMed  Google Scholar 

  38. Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet 2014; 15: 2.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K et al. Excess of rare, inherited truncating mutations in autism. Nat Genet 2015; 47: 582–588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sherva R, Wang Q, Kranzler H, Zhao H, Koesterer R, Herman A et al. Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks. JAMA Psychiatry 2016; 73: 472–480.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Maurin ML, Brisset S, Le Lorc'h M, Poncet V, Trioche P, Aboura A et al. Terminal 14q32.33 deletion: genotype-phenotype correlation. Am J Med Genet A 2006; 140: 2324–2329.

    Article  PubMed  Google Scholar 

  42. Stewart DR, Pemov A, Johnston JJ, Sapp JC, Yeager M, He J et al. Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders. PLoS ONE 2014; 9: e98686.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Franzini M, Fornaciari I, Vico T, Moncini M, Cellesi V, Meini M et al. High-sensitivity gamma-glutamyltransferase fraction pattern in alcohol addicts and abstainers. Drug Alcohol Depend 2013; 127: 239–242.

    Article  CAS  PubMed  Google Scholar 

  44. Wu YW, Prakash KM, Rong TY, Li HH, Xiao Q, Tan LC et al. Lingo2 variants associated with essential tremor and Parkinson's disease. Hum Genet 2011; 129: 611–615.

    Article  CAS  PubMed  Google Scholar 

  45. Vaags AK, Lionel AC, Sato D, Goodenberger M, Stein QP, Curran S et al. Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet 2012; 90: 133–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Demirhan O, Tastemir D . Cytogenetic effects of ethanol on chronic alcohol users. Alcohol Alcohol 2008; 43: 127–136.

    Article  CAS  PubMed  Google Scholar 

  47. Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L et al. A 600kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet 2012; 49: 660–668.

    Article  CAS  PubMed  Google Scholar 

  48. Azen EA, Latreille P, Niece RL . PRBI gene variants coding for length and null polymorphisms among human salivary Ps, PmF, PmS, and Pe proline-rich proteins (PRPs). Am J Hum Genet 1993; 53: 264–278.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Aroor AR, Shukla SD . MAP kinase signaling in diverse effects of ethanol. Life Sci 2004; 74: 2339–2364.

    Article  CAS  PubMed  Google Scholar 

  50. Zamora-Martinez ER, Edwards S . Neuronal extracellular signal-regulated kinase (ERK) activity as marker and mediator of alcohol and opioid dependence. Front Integr Neurosci 2014; 8: 24.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Huang Z, Sjoholm A . Ethanol acutely stimulates islet blood flow, amplifies insulin secretion, and induces hypoglycemia via nitric oxide and vagally mediated mechanisms. Endocrinology 2008; 149: 232–236.

    Article  CAS  PubMed  Google Scholar 

  52. Leggio L, Ray LA, Kenna GA, Swift RM . Blood glucose level, alcohol heavy drinking, and alcohol craving during treatment for alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. Alcohol Clin Exp Res 2009; 33: 1539–1544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hart AB, Engelhardt BE, Wardle MC, Sokoloff G, Stephens M, de Wit H et al. Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13). PLoS ONE 2012; 7: e42646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Curtis D, Vine AE, McQuillin A, Bass NJ, Pereira A, Kandaswamy R et al. Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes. Psychiatr Genet 2011; 21: 1–4.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Dunn AL, Heavner JE, Racz G, Day M . Hyaluronidase: a review of approved formulations, indications and off-label use in chronic pain management. Expert Opin Biol Ther 2010; 10: 127–131.

    Article  CAS  PubMed  Google Scholar 

  56. Park SL, Carmella SG, Chen M, Patel Y, Stram DO, Haiman CA et al. Mercapturic acids derived from the toxicants acrolein and crotonaldehyde in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. PLoS ONE 2015; 10: e0124841.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lasek AW . Effects of ethanol on brain extracellular matrix: implications for alcohol use disorder. Alcohol Clin Exp Res 2016; 40: 2030–2042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim SY, Kim JH, Chung YJ . Effect of combining multiple CNV defining algorithms on the reliability of CNV Calls from SNP genotyping data. Genomics Inform 2012; 10: 194–199.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ehlers CL, Wilhelmsen KC . Genomic scan for alcohol craving in Mission Indians. Psychiatr Genet 2005; 15: 71–75.

    Article  PubMed  Google Scholar 

  60. Schizophrenia Psychiatric Genome-Wide Association Study C. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.

    Article  Google Scholar 

  61. Lee S, Teslovich TM, Boehnke M, Lin X . General framework for meta-analysis of rare variants in sequencing association studies. Am J Hum Genet 2013; 93: 42–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Start-up Fund of The University of Vermont. The raw signal intensity data described in this study were obtained from the database of Genotypes and Phenotypes through accession numbers phs000092 (SAGE), phs000125 (CIDR), and phs000181 (OZALC). The authors acknowledge the Vermont Advanced Computing Core for providing high performance computing resources at the University of Vermont. The authors thank Gina Castellano and Addison Marcus for their very careful review of some reported CNVs. The authors also thank Zoe Furlong for her careful review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, USA

    A Sulovari & D Li

  2. Spine Surgery, Drum Tower Hospital, Nanjing University Medical School,, Nanjing, China

    Z Liu & Z Zhu

  3. Department of Computer Science, University of Vermont, Burlington, VT, USA

    D Li

  4. Neuroscience, Behavior, and Health Initiative, University of Vermont, Burlington, VT, USA

    D Li

Authors
  1. A Sulovari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Z Zhu or D Li.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sulovari, A., Liu, Z., Zhu, Z. et al. Genome-wide meta-analysis of copy number variations with alcohol dependence. Pharmacogenomics J 18, 398–405 (2018). https://doi.org/10.1038/tpj.2017.35

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2017.35

This article is cited by

Search

Advanced search

Quick links