title: NKAIN1-SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent.
abstract: OBJECTIVE
  We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs).
  
  
  METHODS
  A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis.
  
  
  RESULTS
  A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10(-7)≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4×10(-7)) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence.
  
  
  CONCLUSIONS
  NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA. Lingjun.Zuo@yale.edu
authors: Lingjun
authors: L
authors: Zuo
authors: Kesheng
authors: K
authors: Wang
authors: Xiang-Yang
authors: XY
authors: Zhang
authors: John H
authors: JH
authors: Krystal
authors: Chiang-Shan R
authors: CS
authors: Li
authors: Fengyu
authors: F
authors: Zhang
authors: Heping
authors: H
authors: Zhang
authors: Xingguang
authors: X
authors: Luo
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D044465:White People / Q000208:ethnology / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C527493:Nkain1 protein, mouse