Dataset Information

Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA4.

ABSTRACT:

Background

Common variants in the gene GATA binding protein 4 (GATA4) show association with alcohol dependence (AD). The aim of this study was to identify rare variants in GATA4 in order to elucidate the role of this gene in AD susceptibility. Identification of rare variants may provide a more complete picture of the allelic architecture at this risk locus.

Methods

Sanger sequencing of all 6 coding exons of GATA4 was performed in 528 patients and 517 controls. Four in silico prediction tools were used to determine the effect of a DNA variant on the amino acid sequence and protein function. Five variants were included in the replication step. Of these, 4 were successfully genotyped in our replication cohort of 655 patients and 1,501 controls. All patients fulfilled DSM-IV criteria for AD, and all individuals were of German descent.

Results

In the discovery step, 19 different heterozygous variants were identified. Four patient-specific and potentially functionally relevant variants were followed up. Only the variant S379S (c.1137C>T) remained patient specific (1/1,166 patients vs. 0/1,997 controls). None of the variants showed a statistically significant association with AD.

Conclusions

The present study elucidated the role of GATA4 in AD susceptibility by identifying rare variants via Sanger sequencing and subsequent replication. Although novel patient-specific rare variants of GATA4 were identified, none received support in the independent replication step. However, given previous robust findings of association with common variants, GATA4 remains a promising candidate gene for AD.

SUBMITTER: Degenhardt F

PROVIDER: S-EPMC5108491 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA4.

Degenhardt Franziska F Krämer Laurenz L Frank Josef J Treutlein Jens J Heilmann-Heimbach Stefanie S Hecker Julian J Fier Heide Löhlein HL Lang Maren M Witt Stephanie H SH Koller Anna C AC Mann Karl K Hoffmann Sabine S Kiefer Falk F Spanagel Rainer R Rietschel Marcella M Nöthen Markus M MM

Alcoholism, clinical and experimental research 20160704 8

<h4>Background</h4>Common variants in the gene GATA binding protein 4 (GATA4) show association with alcohol dependence (AD). The aim of this study was to identify rare variants in GATA4 in order to elucidate the role of this gene in AD susceptibility. Identification of rare variants may provide a more complete picture of the allelic architecture at this risk locus.<h4>Methods</h4>Sanger sequencing of all 6 coding exons of GATA4 was performed in 528 patients and 517 controls. Four in silico predi ...[more]

PMID: 27374936

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Project description:OBJECTIVES: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. MATERIALS AND 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<?=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). CONCLUSION:We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent.

Dataset Information

Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA4.

Background

Methods

Results

Conclusions

Publications

Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA4.

Similar Datasets

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