期刊
NATURE NEUROSCIENCE
卷 23, 期 7, 页码 809-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41593-020-0643-5
关键词
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资金
- Department of Veterans Affairs Office of Research and Development, Million Veteran Program [I01BX003341, I01CX001849]
- VA Cooperative Studies Program study [575B]
- NIH (NIAAA) [P50 AA12870]
- NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation
- NIH [5T32GM080178, K02DA32573]
- National Institute for Healthcare Research (NIHR) Imperial Biomedical Research Centre (BRC)
- NIDA
- NIMH [MH109532, 1U01MH109514-01]
- NIAAA [U01AA008401]
- Lundbeck Foundation [R102-A9118, R155-2014-1724]
- university of Aarhus
- university of Copenhagen
- Lundbeck Foundation
- Stanley Foundation
- Novo Nordisk Foundation
- NIHR BRC
- UK Medical Research Council [G9623693N, G0500791, G0701007, G1000708]
- NIHR
- Economic and Social Research Council
- University College London Hospitals NHS Foundation Trust NIHR BRC
- university hospital of Aarhus
- university hospital of Copenhagen
- [41910]
- MRC [G0701007, G0500791, MR/M003132/1, G1000708] Funding Source: UKRI
- Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish
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. A genetic study of problematic alcohol use in 435,563 individuals, including data from the Million Veteran Program, Psychiatric Genomics Consortium and UK Biobank, found many novel risk loci and provided new insights into trait biology.
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