A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Common Factor Genomic Structural Equation ModelGenetic variance shared between all three developmental periods is indexed in the common factor. Genetic variance that is distinct from the common factor is indexed in the residuals. Model identification was achieved by fixing the variance of the common factor to one. Factor loadings are labeled with lambda. Residual variances are labeled with epsilon. The model is saturated.

Diagram of the analysis plan in ALSPAC, COGA, and Add HealthThe steps of the analysis plan include data preprocessing, within-sample GWAS, GWAS meta-analysis, estimation of SNP-based heritability and genetic covariances by LD-Score Regression, genomic structural equation modeling with SNP effects, calculation of genetic correlations with other phenotypes, and polygenic risk scoring.

Manhattan plots of gSEM GWAS of total genetic variance in alcohol use frequency in the full sample (ALSPAC, COGA, and Add Health).The genome-wide significance (p<5e-8) is marked in red. The threshold for suggestive significance (p<1e-5) is marked in blue.

Quantile-quantile plots of gSEM GWAS of total genetic variance in alcohol use frequency in the full sample (ALSPAC, COGA, and Add Health).Observed −log10(p) are plotted against the expected uniform distribution of −log10(p) under the null hypothesis.

Genetic correlations between alcohol use frequency at different developmental periods and a series of other phenotypes in the full sample (ALSPAC, COGA, and Add Health).Adolescence, Early Adulthood, and Adulthood refer to the Genomic Structural Equation Model GWAS results using the total variance parameterization of the model The X-axis of the plot is truncated at −1 and 1. A list of the phenotypes with sample sizes and citations is included in Table S3. Abbreviation: AUDIT-P = Alcohol Use Disorder Identification Test, Problems Subscale.

Power estimates for the adolescence residual component of the gSEM at the genome-wide significance threshold (p < 5e-8; left) and the suggestive threshold (p<1e-5; right) with SNP effect size β=0.01Vertical lines in the figure demarcate the observed sample sizes in the discovery analysis of the current study: dotted = adolescence, dot-dashed=early adulthood, dashed = adulthood, solid = common factor.