title: Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent.
abstract: OBJECTIVE
  We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding.
  
  
  METHODS
  A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39,903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0<MAF<0.05 for an association analysis.
  
  
  RESULTS
  Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall, P=1.8×10(-4); VT: overall, P=1.4×10(-4); Collapsing, P=6.5×10(-5)) and European-Australians (Fp: overall, P=0.028; Collapsing, P=0.025), but not in African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in the brain that incorporates serine into lipids. In addition, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (P<0.05). The associations of five of these rare variants that lay within SERINC2 showed region-wide significance (P<α=0.0006) and 25 associations survived correction for a false discovery rate (q<0.05). The associations of two rare variants at SERINC2 were replicated in European-Australians (P<0.05).
  
  
  CONCLUSIONS
  We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zuo
authors.forename: Ke-Sheng
authors.initials: KS
authors.lastname: Wang
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhang
authors.forename: Chiang-Shan R
authors.initials: CS
authors.lastname: Li
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Wenan
authors.initials: W
authors.lastname: Chen
authors.forename: Guimin
authors.initials: G
authors.lastname: Gao
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
mesh_terms: D001741:Black or African American / Q000235:genetics; D000437:Alcoholism / Q000150:complications / Q000235:genetics*; D001315:Australia; D016022:Case-Control Studies; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D001523:Mental Disorders / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012307:Risk Factors; D044465:White People / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C585495:SERINC2 protein, human