期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 17, 页码 7119-7124出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1017288108
关键词
genome-wide analysis; epidemiologic; transcriptional expression analysis
资金
- European Union [HEALTH-F4-2007-201413, LSHM-CT-2007-037286, 242257]
- United Kingdom National Institute for Health Research (NIHR) Biomedical Research Centre Mental Health, the Medical Research Council [93558]
- German Nationales Genomforschungsnetz [01GS08152]
- State of California for Medical Research through the University of California, San Francisco
- Research Council United Kingdom (RCUK)
- Imperial College Healthcare NHS Trust Comprehensive Biomedical Research Centre
- NIHR
- Swedish Council for Working Life and Social Research (FAS)
- Swedish Science Research Council
- Instituto de Salud Carlos III (ISCIII) [FIS PI021570]
- Junta de Castilla y Leon (JCyL) [SA044A08, GR93]
- RTICC, ISCIII, Spain [RD06/0020/000]
- MRC [MC_U106188470, G0601966, G0801056, G0700931, G0701863, G0901858, G0600676] Funding Source: UKRI
- Medical Research Council [G1000143, G0700931, G0801056, G0600676, MC_U106179471, MC_U106188470, G0901858, G0801056B, G0601966, G0701863, G9817803B, G0401527] Funding Source: researchfish
Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
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