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
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/7/1
Y1 - 2020/7/1
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.
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U2 - 10.1038/s41593-020-0643-5
DO - 10.1038/s41593-020-0643-5
M3 - Article
C2 - 32451486
AN - SCOPUS:85085522562
SN - 1097-6256
VL - 23
SP - 809
EP - 818
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 7
ER -
