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Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA 4
Author(s) -
Degenhardt Franziska,
Krämer Laurenz,
Frank Josef,
Treutlein Jens,
HeilmannHeimbach Stefanie,
Hecker Julian,
Fier Heide Löhlein,
Lang Maren,
Witt Stephanie H.,
Koller Anna C.,
Mann Karl,
Hoffmann Sabine,
Kiefer Falk,
Spanagel Rainer,
Rietschel Marcella,
Nöthen Markus M.
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13125
Subject(s) - sanger sequencing , genetics , gene , biology , in silico , locus (genetics) , allele , dna sequencing , exon
Background Common variants in the gene GATA binding protein 4 ( GATA 4 ) show association with alcohol dependence ( AD ). The aim of this study was to identify rare variants in GATA 4 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 GATA 4 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 GATA 4 in AD susceptibility by identifying rare variants via Sanger sequencing and subsequent replication. Although novel patient‐specific rare variants of GATA 4 were identified, none received support in the independent replication step. However, given previous robust findings of association with common variants, GATA 4 remains a promising candidate gene for AD .