Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.
- Authors
- Adkins, Daniel E; Clark, Shaunna L; Copeland, William E; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A; Silberg, Judy; Brown, Tyson H; Fergusson, David M; Horwood, L John; Eaves, Lindon; van den Oord, Edwin J C G; Sullivan, Patrick F; Costello, E J
- Year
- 2015
- Journal
- Twin research and human genetics : the official journal of the International Society for Twin Studies
- PMID
- 26081443
- DOI
- 10.1017/thg.2015.36
- PMCID
- PMC4762598
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.
A) QQ plots and B) Manhattan plots for GWAS results of two longitudinal alcohol consumption measures.
| Name | Type |
|---|---|
| ADHD | phenotype |
| ADRA2A | gene |
| adult human height local | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| Alcohol consumption (drinks per week) local | phenotype |
| alcohol-induced liver toxicity local | phenotype |
| alcohol intoxication | phenotype |
| alcohol withdrawal | phenotype |
| ANK3 | gene |
| anxiety | phenotype |
| blood pressure | phenotype |
| celecoxib | drug |
| Christchurch Health and Development Study | cohort |
| CNS | anatomy |
| Cortical excitability/inhibition local | phenotype |
| craving | phenotype |
| dependence | phenotype |
| developmental consumption trajectory local | phenotype |
| developmental trajectory | phenotype |
| Developmental trajectory of alcohol consumption local | phenotype |
| European ancestry | cohort |
| GABA | phenotype |
| Gabbr2 | gene |
| Gabrg2 | gene |
| Gabrg3 | gene |
| GEDI | cohort |
| GEDI GWAS samples local | cohort |
| gene | gene |
| genes | gene |
| genotype dosages local | drug |
| GLUL | gene |
| glycemic phenotype | phenotype |
| GRIK1 | gene |
| GRIK5 | gene |
| GRIN2B | gene |
| GSMS local | cohort |
| hangover intensity local | phenotype |
| HapMap3 | cohort |
| HNF4A local | gene |
| HNF4G local | gene |
| IGSF9B local | gene |
| Illumina Human660W-Quad v1 DNA Analysis BeadChips local | drug |
| KCNJ3 | gene |
| LOC100129340 local | gene |
| Longitudinal phenotypic assessments local | phenotype |
| Mayo Clinic | cohort |
| mean adolescent alcohol consumption local | phenotype |
| mean adolescent consumption local | phenotype |
| Mean alcohol consumption local | phenotype |
| mean consumption local | phenotype |
| MIPOL1 local | gene |
| Non-normative drinking local | phenotype |
| Polymorphism | cohort |
| ProbABEL | drug |
| Prostaglandins | drug |
| psychiatric disorders | phenotype |
| Psychiatric GWAS local | cohort |
| ROBO1 | gene |
| ROBO2 local | gene |
| rs11710497 local | variant |
| rs12257178 local | variant |
| rs17053864 local | variant |
| rs1984450 local | variant |
| rs4898641 local | variant |
| rs6778281 local | variant |
| rs694424 local | variant |
| rs7019589 local | variant |
| rs7031417 local | variant |
| rs7253326 local | variant |
| SLC6A1 | gene |
| SNP | cohort |
| substance abuse | phenotype |
| trajectory outcome local | phenotype |
| VTSABD local | cohort |
| ZNF578 local | gene |
| ZNF701 local | gene |
| ZNF808 local | gene |
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