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 6 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. 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.

The Rate of Change in Alcohol Misuse Across Adolescence is Heritable

“…We selected markers with p <0.0001 (a threshold chosen to balance statistical support and sample size) for comparison to results reported by Adkins and colleagues (Adkins et al, 2015). Of 9397 markers selected, target sample results were available for 1141 due to the use of different imputation reference panels across studies.…”

“…We selected promising ( p <0.0001) markers for individual SNP-based replication attempts using the only available published study of a similar phenotype (Adkins et al, 2015). P-values were combined across the current study and the meta-analytic results from Adkins et al, using Fisher’s method.…”

“…To our knowledge, only one prior study has examined genetic influences underlying changes in alcohol outcomes over time. In a study involving three US cohorts longitudinally assessed from childhood into young adulthood, Adkins and colleagues (2015) modeled developmental trajectories of alcohol consumption, followed by genome-wide association analysis of the resulting slope parameter. Results were meta-analyzed across cohorts, and while no marker met genome-wide significance criteria for association with the slope, biologically plausible suggestive markers were identified, and secondary analyses implicated genes involved in axon guidance and development.…”

“…We employ data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospectively assessed cohort study in the southwest UK, to quantify growth in alcohol misuse from adolescence to emerging adulthood. As only one prior study has subjected a comparable outcome to genetic analysis (Adkins et al, 2015), the current study represents a relatively novel approach to conceptualizing the genetic risk of alcohol use problems.…”

Developmental Etiologies of Alcohol Use and Their Relations to Parent and Peer Influences Over Adolescence and Young Adulthood: A Genetically Informed Approach

“…Few twin models estimate multiple genetic and/or environment factors (e.g., Adkins et al, 2015; Edwards et al, 2016), or include age-specific etiologies over development. Those that do so present mixed results on age-specific latent etiologies.…”