Investigation of Association of Rare, Functional Genetic Variants With Heavy Drinking and Problem Drinking in Exome Sequenced UK Biobank Participants

Aims The study aimed to identify specific genes and functional genetic variants affecting susceptibility to two alcohol-related phenotypes: heavy drinking and problem drinking. Methods Phenotypic and exome sequence data were downloaded from the UK Biobank. Reported drinks in the last 24 hours were used to define heavy drinking, while responses to a mental health questionnaire defined problem drinking. Gene-wise weighted burden analysis was applied, with genetic variants which were rarer and/or had a more severe functional effect being weighted more highly. Additionally, previously reported variants of interest were analysed inidividually. Results Of exome sequenced subjects, for heavy drinking, there were 8166 cases and 84,461 controls, while for problem drinking, there were 7811 cases and 59,606 controls. No gene was formally significant after correction for multiple testing, but three genes possibly related to autism were significant at P < 0.001, FOXP1, ARHGAP33 and CDH9, along with VGF which may also be of psychiatric interest. Well established associations with rs1229984 in ADH1B and rs671 in ALDH2 were confirmed, but previously reported variants in ALDH1B1 and GRM3 were not associated with either phenotype. Conclusions This large study fails to conclusively implicate any novel genes or variants. It is possible that more definitive results will be obtained when sequence data for the remaining UK Biobank participants become available and/or if data can be obtained for a more extreme phenotype such as alcohol dependence disorder. This research has been conducted using the UK Biobank Resource. Short Summary: Tests for association of rare, functional genetic variants with heavy drinking and problem drinking confirm the known effects of variants in ADH1B and ALDH2 but fail to implicate novel variants or genes. Results for three genes potentially related to autism suggest that they might exert a protective effect.

Automated summary

This study did not conclusively implicate any novel genes or variants. The known effects of variants in ADH1B and ALDH2 on heavy drinking and problem drinking were confirmed, while novel variants or genes were not identified. Results suggesting potential protective effects of three genes related to autism were observed.