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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: African Americans, Alcoholism, Australia, Case-Control Studies, European Continental Ancestry Group, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Humans, Membrane Proteins, Mental Disorders, Nervous System Diseases, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors.
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Are rare SERINC2 variants specific for alcohol dependence in individuals of European descent? Context: 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. 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. 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).
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We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent. Final Decision: yes