title: Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.
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.
authors.affiliation: Center for Biomarker Research and Personalized Medicine,Virginia Commonwealth University,School of Pharmacy,Richmond,Virginia,USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Adkins
authors.affiliation: Center for Biomarker Research and Personalized Medicine,Virginia Commonwealth University,School of Pharmacy,Richmond,Virginia,USA.
authors.forename: Shaunna L
authors.initials: SL
authors.lastname: Clark
authors.affiliation: Department of Psychiatry,Duke University Medical Center,Durham,North Carolina,USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Copeland
authors.affiliation: Department of Pathology,University of Otago,Christchurch,New Zealand.
authors.forename: Martin
authors.initials: M
authors.lastname: Kennedy
authors.affiliation: Division of Epidemiology,Services and Prevention Research,National Institute on Drug Abuse,Bethesda,Maryland,USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Conway
authors.affiliation: Department of Psychiatry,Duke University Medical Center,Durham,North Carolina,USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Angold
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University,Richmond,Virginia,USA.
authors.forename: Hermine
authors.initials: H
authors.lastname: Maes
authors.affiliation: Thurston Arthritis Research Center,University of North Carolina at Chapel Hill,Chapel Hill,North Carolina,USA.
authors.forename: Youfang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Biomarker Research and Personalized Medicine,Virginia Commonwealth University,School of Pharmacy,Richmond,Virginia,USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Department of Psychiatry,Duke University Medical Center,Durham,North Carolina,USA.
authors.forename: Alaattin
authors.initials: A
authors.lastname: Erkanli
authors.affiliation: Department of Psychiatry,Duke University Medical Center,Durham,North Carolina,USA.
authors.forename: Ashwin A
authors.initials: AA
authors.lastname: Patkar
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University,Richmond,Virginia,USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Silberg
authors.affiliation: Center for Medicine,Health and Society,Vanderbilt University,Nashville,Tennessee,USA.
authors.forename: Tyson H
authors.initials: TH
authors.lastname: Brown
authors.affiliation: Department of Psychological Medicine,University of Otago,Christchurch,New Zealand.
authors.forename: David M
authors.initials: DM
authors.lastname: Fergusson
authors.affiliation: Department of Psychological Medicine,University of Otago,Christchurch,New Zealand.
authors.forename: L John
authors.initials: LJ
authors.lastname: Horwood
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University,Richmond,Virginia,USA.
authors.forename: Lindon
authors.initials: L
authors.lastname: Eaves
authors.affiliation: Center for Biomarker Research and Personalized Medicine,Virginia Commonwealth University,School of Pharmacy,Richmond,Virginia,USA.
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
authors.affiliation: Departments of Genetics and Psychiatry,University of North Carolina at Chapel Hill,Chapel Hill,North Carolina,USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Department of Psychiatry,Duke University Medical Center,Durham,North Carolina,USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Costello
mesh_terms: D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics; D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; C493413:SLC6A1 protein, human; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human
keywords: GABA; SLC6A1; alcohol; developmental trajectory; genome-wide; longitudinal