SA114 - GENETIC ETIOLOGY OF SELF-RATING OF THE EFFECTS OF ALCOHOL (SRE) SCORES IN YOUNG ADULTS

Abstract

Background Alcohol misuse is a significant public health concern with social, medical, and economic consequences. Previous studies suggest that initial sensitivity to alcohol may impact use of the substance: those with low sensitivity may drink more, potentially establishing unhealthy drinking habits that persist into adulthood. The Self-Rating of the Effects of Alcohol (SRE) scale was developed to quantify initial sensitivity to alcohol, and SRE scores have been positively associated with concurrent and later drinking behaviors. Furthermore, evidence suggests that SRE scores are influenced by familial factors, raising the possibility that genetic liability to low alcohol sensitivity may increase risk of later alcohol misuse. We sought to clarify the role of genetic factors on SRE scores in two samples of young adults. Methods We derived SRE scores in two population-based cohort studies. ALSPAC participants were born between 1991–1992 in the southwest region of England and have been assessed at least once per year since birth. SRE scores were derived based on assessments at ages 15.5, 16.5, and 17.5. S4S participants were students at a large, public, urban university in the southeastern US, enrolled during the fall or spring of their freshman year (2011–2013), and assessed each subsequent spring. Participants were of diverse ancestry and were 18+ years of age at initial enrollment. The first available SRE score was used for subsequent analyses. Phenotypic and genotypic data meeting all quality control filters were available for a total of N=7339 participants. We conducted Genome-Wide Association Studies (GWAS) within each sample/ancestry group, using ancestry-informative principal components, sex, and age at first available SRE assessment as covariates. Initial GWAS results were meta-analyzed in METAL. SNP-based heritabilities for each sample/ancestry group were estimated in GCTA. Additional secondary analyses were conducted in VEGAS and JEPEGMIX2. Results A total of 15,642,250 markers were analyzed in at least one group. No individual marker met genome-wide significance criteria. The top marker, rs146298733 (p=3.16e-07), mapped to an intron in DLGAP1, variants in which have been previously associated with psychiatric outcomes including major depression and obsessive-compulsive disorder. Meta-analysis of GCTA results indicated that SRE is modestly heritable (h2SNP=0.19, SE=0.10), though this was driven primarily by the ALSPAC sample, for which assessments were prospective. Pathway analyses implicated the GABAergic system and genes related to thromboxane signaling, both of which have been associated with alcohol-related phenotypes. Discussion We present evidence consistent with prior reports that initial sensitivity to alcohol is influenced by genetic factors. Preliminary analyses implicate systems known to influence other alcohol phenotypes and provide novel targets for future analysis. Implicated loci and aggregate genetic risk should be confirmed in independent samples. Heterogeneity across samples suggests that assessment methods are important to SRE measurement, which may have implications for genetic analyses. Further characterization of genetic influences may elucidate mechanisms underlying the pathway from initial sensitivity to alcohol problems.