Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits

TY - JOUR

T1 - Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits

AU - Zhou, Hang

AU - Sealock, Julia M

AU - Sanchez-Roige, Sandra

AU - Clarke, Toni-Kim

AU - Levey, Daniel F

AU - Cheng, Zhongshan

AU - Li, Boyang

AU - Polimanti, Renato

AU - Kember, Rachel L

AU - Smith, Rachel Vickers

AU - Thygesen, Johan H

AU - Morgan, Marsha Y

AU - Atkinson, Stephen R

AU - Thursz, Mark R

AU - Nyegaard, Mette

AU - Mattheisen, Manuel

AU - Børglum, Anders D

AU - Johnson, Emma C

AU - Justice, Amy C

AU - Palmer, Abraham A

AU - McQuillin, Andrew

AU - Davis, Lea K

AU - Edenberg, Howard J

AU - Agrawal, Arpana

AU - Kranzler, Henry R

AU - Gelernter, Joel

PY - 2020/7

Y1 - 2020/7

N2 - Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

AB - Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

KW - ASSOCIATION

KW - BIOBANK

KW - DEPENDENCE

KW - DISORDER

KW - GWAS

KW - HERITABILITY

KW - LD SCORE REGRESSION

KW - LOCI

KW - MENDELIAN RANDOMIZATION

KW - RISK

U2 - 10.1038/s41593-020-0643-5

DO - 10.1038/s41593-020-0643-5

M3 - Journal article

C2 - 32451486

SN - 1097-6256

VL - 23

SP - 809

EP - 818

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 7

ER -