A haplotype of glycogen synthase kinase 3β is associated with early onset of unipolar major depression

Recent findings suggest that glycogen synthase kinase 3 beta (GSK3 beta) may play a role in the pathophysiology and treatment of mood disorders. Various genetic studies have shown the association of GSK3 beta polymorphisms with different mood disorder phenotypes. We hypothesized that genetic variants in the GSK3 beta gene could partially underlie the susceptibility to mood disorders. We performed a genetic case-control study of 440 psychiatrically screened control subjects and 445 mood disorder patients [256 unipolar major depressive disorder (MDD) and 189 bipolar disorder (BD)]. We genotyped a set of 11 single nucleotide polymorphisms (SNPs) and determined the relative frequency of a known copy number variant (CNV) overlapping the GSK3 beta by quantitative real-time polymerase chain reaction (PCR). We found no evidence of association with MDD or BD diagnosis, and we further investigated the age at onset (AAO) of the disorder and severity of depressive index episode. We found that rs334555, located in intron 1 of GSK3 beta, was nominally associated with an earlier AAO of the disease in MDD (P = 0.001). We also identified a haplotype containing three SNPs (rs334555, rs119258668 and rs11927974) associated with AAO of the disorder (permutated P = 0.0025). We detected variability for the CNV, but we could not detect differences between patients and controls for any of the explored phenotypes. This study presents further evidence of the contribution of GSK3 beta to mood disorders, implicating a specific SNP and a haplotype with an earlier onset of the disorder in a group of well-characterized patients with unipolar MDD. Further replication studies in patients with the same phenotypic characteristics should confirm the results reported here.