Skip to main content Accessibility help
×
×
Home

Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood

  • Daniel E. Adkins (a1), Shaunna L. Clark (a1), William E. Copeland (a2), Martin Kennedy (a3), Kevin Conway (a4), Adrian Angold (a2), Hermine Maes (a5), Youfang Liu (a6), Gaurav Kumar (a1), Alaattin Erkanli (a2), Ashwin A. Patkar (a2), Judy Silberg (a5), Tyson H. Brown (a7), David M. Fergusson (a8), L. John Horwood (a8), Lindon Eaves (a5), Edwin J. C. G. van den Oord (a1), Patrick F. Sullivan (a9) and E. J. Costello (a2)...

Abstract

The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N = 2,126, obs = 12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR < 0.1) and six others met our ‘suggestive’ criterion (FDR <0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood
      Available formats
      ×

Copyright

Corresponding author

address for correspondence: Dr Daniel E. Adkins, Center for Biomarker Research and Precision Medicine, School of Pharmacy, Virginia Commonwealth University, McGuire Hall, Room 216B, PO Box 980533, Richmond, VA 23298-0581, USA. E-mail: deadkins@vcu.edu

References

Hide All
Adkins, D. E., Aberg, K., McClay, J. L., Bukszar, J., Zhao, Z., Jia, P., . . . van den Oord, E. J. (2011). Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Molecular Psychiatry, 16, 321332.
Adkins, D. E., Aberg, K., McClay, J. L., Hettema, J. M., Kornstein, S. G., Bukszar, J., . . . van den Oord, E. J. (2010). A genomewide association study of citalopram response in major depressive disorder — A psychometric approach. Biological Psychiatry, 68, e2527.
Adkins, D. E., Daw, J. K., McClay, J. L., & Van den Oord, E. (2012). The influence of five monoamine genes on trajectories of depressive symptoms across adolescence and young adulthood. Development and Psychopathology, 24, 267285.
Agrawal, A., Freedman, N. D., Cheng, Y. C., Lin, P., Shaffer, J. R., Sun, Q., . . . Beirut, L., for the GENEVA Consortium. (2012). Measuring alcohol consumption for genomic meta-analyses of alcohol intake: Opportunities and challenges. American Journal of Clinical Nutrition, 95, 539547.
Alfos, S., Higueret, P., Pallet, V., Higueret, D., Garcin, H., & Jaffard, R. (1996). Chronic ethanol consumption increases the amount of mRNA for retinoic acid and triiodothyronine receptors in mouse brain. Neuroscience Letters, 206, 7376.
Angold, A., & Costello, E. (2000). The child and adolescent psychiatric assessment (CAPA). Journal of the American Academy of Child and Adolescent Psychiatry, 39, 3948.
Aryal, P., Dvir, H., Choe, S., & Slesinger, P. A. (2009). A discrete alcohol pocket involved in GIRK channel activation. Nature Neuroscience, 12, 988995.
Aulchenko, Y. S., Struchalin, M. V., & van Duijn, C. M. (2010). ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics, 11, 134.
Beecham, G. W., Martin, E. R., Li, Y. J., Slifer, M. A., Gilbert, J. R., Haines, J. L., . . . Pericak-Vance, M. A. (2009). Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. American Journal of Human Genetics, 84, 3543.
Benjamini, Y. & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289300.
Bierut, L. J., Agrawal, A., Bucholz, K. K., Doheny, K. F., Laurie, C., Pugh, E., . . . Rice, J. P. & as part of the gene, environment association studies (GENEVA) Consortium (2010). A genome-wide association study of alcohol dependence. Proceedings of the National Academy of Sciences, 107, 50825087.
Bollen, K. A., & Curran, P. J. (2005). Latent curve models: A structural equation perspective. Hoboken, NJ: John Wiley & Sons.
Brown, B. W., & Russell, K. (1997). Methods correcting for multiple testing: Operating characteristics. Statistics in Medicine, 16, 25112528.
Burnham, K. P., & Anderson, D. R. (2004). Multimodel inference — Understanding AIC and BIC in model selection. Sociological Methods & Research, 33, 261304.
Chen, K., & Kandel, D. B. (1995). The natural history of drug use from adolescence to the mid-thirties in a general population sample. American Journal of Public Health, 85, 4147.
Clark, S. L., Adkins, D. E., Aberg, K., Hettema, J. M., McClay, J. L., Souza, R. P., . . . van den Oord, E. (2012). Pharmacogenomic study of side-effects for antidepressant treatment options in STAR*D. Psychological Medicine, 42, 11511162.
Clarke, T. K., Dempster, E., Docherty, S. J., Desrivieres, S., Lourdsamy, A., Wodarz, N., . . . Schumann, G. (2012). Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse. Addiction Biology, 17, 202208.
Cohen, J. (1983). The cost of dichotomization. Applied Psychological Measurement, 7, 249253.
Costello, E. J., Angold, A., Burns, B., Stangl, D., Tweed, D., Erkanli, A., . . . Worthman, C. (1996). The Great Smoky Mountains Study of Youth: Goals, designs, methods, and the prevalence of DSM-III-R disorders. Archives of General Psychiatry, 53, 11291136.
de Bakker, P. I. W., Ferreira, M. A. R., Jia, X., Neale, B. M., Raychaudhuri, S., & Voight, B. F. (2008). Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Human Molecular Genetics, 17, R122R128.
Dubois, P. C. A., Trynka, G., Franke, L., Hunt, K. A., Romanos, J., Curtotti, A., . . . van Heel, D. A. (2010). Multiple common variants for celiac disease influencing immune gene expression. Nature Genetics, 42, 295302.
Edenberg, H. J., Koller, D. L., Xuei, X., Wetherill, L., McClintick, J. N., Almasy, L., . . . Foroud, T. (2010). Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcoholism: Clinical and Experimental Research, 34, 840852.
Fergusson, D., & Horwood, L. (2001). The Christchurch health and development study: Review of findings on child and adolescent mental health. Australian and New Zealand Journal of Psychiatry, 35, 287296.
Grant, J. D., Agrawal, A., Bucholz, K. K., Madden, P. A. F., Pergadia, M. L., Nelson, E. C., . . . Heath, A. C. (2009). Alcohol consumption indices of genetic risk for alcohol dependence. Biological Psychiatry, 66, 795800.
Gudbjartsson, D. F., Walters, G. B., Thorleifsson, G., Stefansson, H., Halldorsson, B. V., Zusmanovich, P., . . . Stefansson, K. (2008). Many sequence variants affecting diversity of adult human height. Nature Genetics, 40, 609615.
Harford, T. C., Grant, B. F., Yi, H. Y., & Chen, C. M. (2005). Patterns of DSM-IV alcohol abuse and dependence criteria among adolescents and adults: Results from the 2001 National Household Survey on Drug Abuse. Alcoholism Clinical and Experimental Research, 29, 810828.
Hata, A. N., & Breyer, R. M. (2004). Pharmacology and signaling of prostaglandin receptors: Multiple roles in inflammation and immune modulation. Pharmacology & Therapeutics, 103, 147166.
Heath, A. C., Whitfield, J. B., Martin, N. G., Pergadia, M. L., Goate, A. M., Lind, P. A., . . . Montgomery, G. W. (2011). A quantitative-trait genome-wide association study of alcoholism risk in the community: Findings and implications. Biological Psychiatry, 70, 513518.
Hirotsune, S., Yoshida, N., Chen, A., Garrett, L., Sugiyama, F., Takahashi, S., . . . Yoshiki, A. (2003). An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Nature, 423, 9196.
Johnson, C., Drgon, T., Liu, Q.-R., Walther, D., Edenberg, H., Rice, J., Foroud, T., . . . Uhl, G. R. (2006). Pooled association genome scanning for alcohol dependence using 104,268 SNPs: Validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 141B, 844853.
Kamburov, A., Pentchev, K., Galicka, H., Wierling, C., Lehrach, H., & Herwig, R. (2011). ConsensusPathDB: Toward a more complete picture of cell biology. Nucleic Acids Research, 39, D712D717.
Kendler, K. S., Schmitt, E., Aggen, S. H., & Prescott, C. A. (2008). Genetic and environmental influences on alcohol, caffeine, cannabis, and nicotine use from early adolescence to middle adulthood. Archives of General Psychiatry, 65, 674682.
Khatri, P., Sirota, M., Butte, A. J. (2012). Ten Years of Pathway Analysis: Current Approaches and Outstanding Challenges. PLoS Computational Biology, 8, e1002375.
Kim, B. N., Kim, J. W., Kang, H., Cho, S. C., Shin, M. S., Yoo, H. J., Hong, S. B., . . . Lee, D. S. (2010). Regional differences in cerebral perfusion associated with the alpha-2A-adrenergic receptor genotypes in attention deficit hyperactivity disorder. Journal of Psychiatry & Neuroscience, 35, 330336.
Laird, N. M., & Ware, J. H. (1982). Random-effects models for longitudinal data. Biometrics, 38, 963974.
Lasky-Su, J., Neale, B. M., Franke, B., Anney, R. J., Zhou, K., Maller, J. B., . . . Faraone, S. V. (2008). Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 13451354.
Lewohl, J. M., Wilson, W. R., Mayfield, R. D., Brozowski, S. J., Morrisett, R. A., & Harris, R. A. (1999). G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nature Neuroscience, 2, 10841090.
Li, Y., Willer, C. J., Ding, J., Scheet, P., & Abecasis, G. R. (2010). MaCH: Using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genetic Epidemiology, 34, 816834.
McClay, J. L., Adkins, D. E., Aberg, K., Bukszar, J., Khachane, A. N., Keefe, R. S. E., . . . van den Oord, E. (2011a). Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. Neuropsychopharmacology, 36, 616626.
McClay, J. L., Adkins, D. E., Aberg, K., Stroup, S., Perkins, D. O., Vladimirov, V. I., . . . van den Oord, E. (2011b). Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Molecular Psychiatry, 16, 7685.
Merenakk, L., Maestu, J., Nordquist, N., Parik, J., Oreland, L., Loit, H. M., . . . Harro, J. (2011). Effects of the serotonin transporter (5-HTTLPR) and alpha(2A)-adrenoceptor (C-1291G) genotypes on substance use in children and adolescents: A longitudinal study. Psychopharmacology, 215, 1322.
Miles, D., Silberg, J., Pickens, R., & Eaves, L. (2005). Familial influences for alcohol use in adolescent female twins: Genetic and environmental interactions. Journal of Studies on Alcohol, 66, 445451.
Mokdad, A. H., Marks, J. S., Stroup, D. F., & Gerberding, J. L. (2004). Actual causes of death in the United States, 2000. JAMA, 291, 12381245.
Nanji, A. A., Khettry, U., Sadrzadeh, S. M. H., & Yamanaka, T. (1993). Severity of liver-injury in experimental alcoholic liver-disease — Correlation with plasma endotoxin, prostaglandin-E2, leukotriene-B4, and thromboxane-B2. American Journal of Pathology, 142, 367373.
Ozsoy, S., Esel, E., Izgi, H. B., & Sofuoglu, S. (2006). Thyroid function in early and late alcohol withdrawal: Relationship with aggression, family history, and onset age of alcoholism. Alcohol and Alcoholism, 41, 515521.
Pagan, J. L., Rose, R. J., Viken, R. J., Pulkkinen, L., Kaprio, J., & Dick, D. M. (2006). Genetic and environmental influences on stages of alcohol use across adolescence and into young adulthood. Behavior Genetics, 36, 483497.
Patterson, N., Price, A. L., & Reich, D. (2006). Population structure and eigenanalysis. PLoS Genetics, 2, e190.
Penning, T. D., Talley, J. J., Bertenshaw, S. R., Carter, J. S., Collins, P. W., Docter, S., . . . Isakson, P. C. (1997). Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4- 5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl benzenesulfona mide (SC-58635, Celecoxib). Journal of Medicinal Chemistry, 40, 13471365.
Pinheiro, J. C., & Bates, D. M. (2000). Mixed-effects models in S and S-plus. New York, NY: Springer.
Prestes, A. P., Marques, F. Z. C., Hutz, M. H., Roman, T., & Bau, C. H. D. (2007). Tobacco smoking and the ADRA2A C-1291G polymorphism. Journal of Neural Transmission, 114, 15031506.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., . . . Sham, P. C. (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics, 81, 559575.
Quertemont, E. (2004). Genetic polymorphism in ethanol metabolism: Acetaldehyde contribution to alcohol abuse and alcoholism. Molecular Psychiatry, 9, 570581.
Roman, T., Polanczyk, G. V., Zeni, C., Genro, J. P., Rohde, L. A., & Hutz, M. H. (2005). Further evidence of the involvement of alpha-2A-adrenergic receptor gene (ADRA2A) in inattentive dimensional scores of attention-deficit//hyperactivity disorder. Molecular Psychiatry, 11, 810.
Roman, T., Schmitz, M., Polanczyk, G. V., Eizirik, M., Rohde, L. A. & Hutz, M. H. (2003). Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder? American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 120B (1), 116–20.
Rutter, M., Silberg, J., O’Connor, T., & Simonoff, E. (1999). Genetics and child psychiatry: II — Empirical research findings. Journal of Child Psychology and Psychiatry, 40, 1955.
Schumann, G., Coin, L. J., Lourdusamy, A., Charoen, P., Berger, K. H., Stacey, D., . . . Elliott, P. (2011). Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proceedings of the National Academy of Sciences, 108, 71197124.
Silberg, J., Rutter, M., D’Onofrio, B., & Eaves, L. (2003). Genetic and environmental risk factors in adolescent substance use. Journal of Child Psychology & Psychiatry & Allied Disciplines, 44, 664676.
Simonoff, E., Pickles, A., Meyer, J. M., Silberg, J. L., Maes, H. H., Loeber, R., . . . Eaves, L. J. (1997). The Virginia twin study of adolescent behavioral development: Influences of age, sex, and impairment on rates of disorder. Archives of General Psychiatry, 54, 801808.
Singer, J. D. (2003). Applied longitudinal data analysis: Modeling change and event occurrence. Oxford, New York: Oxford University Press.
Storey, J. D., & Tibshirani, R. (2003). Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America, 100, 94409445.
Talmud, P. J., Cooper, J. A., Gaunt, T., Holmes, M. V., Shah, S., Palmen, J., . . . Humphries, S. E. (2011). Variants of ADRA2A are associated with fasting glucose, blood pressure, body mass index and type 2 diabetes risk: Meta-analysis of four prospective studies. Diabetologia, 54, 17101719.
Tam, O. H., Aravin, A. A., Stein, P., Girard, A., Murchison, E. P., Cheloufi, S., . . . Hannon, G. J. (2008). Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature, 453, 534538.
The Wellcome Trust Case Control Consortium. (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447, 661678.
Thoeringer, C. K., Erhardt, A., Sillaber, I., Mueller, M. B., Ohl, F., Holsboer, F., . . . Keck, M. E. (2010). Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice. Journal of Psychopharmacology, 24, 733743.
Thoeringer, C. K., Ripke, S., Unschuld, P. G., Lucae, S., Ising, M., Bettecken, T., . . . Erhardt, A. (2009). The GABA transporter 1 (SLC6A1): A novel candidate gene for anxiety disorders. Journal of Neural Transmission, 116, 649657.
Treutlein, J., Cichon, S., Ridinger, M., Wodarz, N., Soyka, M., Zill, P., . . . Rietschel, M. (2009). Genome-wide association study of alcohol dependence. Archives of General Psychiatry, 66, 773784.
van den Oord, E. J., Adkins, D. E., McClay, J., Lieberman, J., & Sullivan, P. F. (2009). A systematic method for estimating individual responses to treatment with antipsychotics in CATIE. Schizophrenia Research, 107, 1321.
van der Sluis, S., Posthuma, D., Nivard, M. G., Verhage, M., & Dolan, C. V. (2013). Power in GWAS: Lifting the curse of the clinical cut-off. Molecular Psychiatry, 18, 23.
Vengeliene, V., Bilbao, A., Molander, A., & Spanagel, R. (2008). Neuropharmacology of alcohol addiction. British Journal of Pharmacology, 154, 299315.
Waldman, I. D., Nigg, J. T., Gizer, I. R., Park, L., Rappley, M. D., & Friderici, K. (2006). The adrenergic receptor alpha-2A gene (ADRA2A) and neuropsychological executive functions as putative endophenotypes for childhood ADHD. Cognitive Affective & Behavioral Neuroscience, 6, 1830.
Whitelaw, N. C., & Whitelaw, E. (2006). How lifetimes shape epigenotype within and across generations. Human Molecular Genetics, 15, R131R137.
WHO. (2011). Global status report on alcohol and health. Geneva: Author.
Wiese, J. G., Shlipak, M. G., & Browner, W. S. (2000). The alcohol hangover. Annals of Internal Medicine 132, 897902.
Willett, J. B., Singer, J. D., & Martin, N. C. (1998). The design and analysis of longitudinal studies of development and psychopathology in context: Statistical models and methodological recommendations. Development and Psychopathology, 10, 395426.
Zuo, L., Gelernter, J., Zhang, C. K., Zhao, H., Lu, L., Kranzler, H. R., . . . Luo, X. (2011). Genome-wide association study of alcohol dependence implicates KIAA0040 on chromosome 1q. Neuropsychopharmacology, 37, 557566.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Twin Research and Human Genetics
  • ISSN: 1832-4274
  • EISSN: 1839-2628
  • URL: /core/journals/twin-research-and-human-genetics
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Type Description Title
PDF
Supplementary materials

Adkins supplementary material
Adkins supplementary material 1

 PDF (2.3 MB)
2.3 MB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed