Resequencing Three Candidate Genes for Major Depressive Disorder in a Dutch Cohort

Abstract

Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07) than in the GAIN-MDD GWAS (P = 0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort.

Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences

“…Although the initial GWAS reported suggestive evidence for PCLO (Sullivan et al, 2009), and subsequent studies have reported an association with MDD (Hek et al, 2010, Aragam et al, 2011, Woudstra et al, 2012Verbeek et al, 2013), the association was not supported by results from subsequent GWAS studies (Lewis et al, 2010;Muglia et al, 2010;Rietschel et al, 2010;Kohli et al, 2011;Shi et al, 2011;Shyn et al, 2011;Wray et al, 2012), or from the recently published mega-analysis (Ripke et al, 2013) including 9240 MDD cases and 9519 controls. Based on these studies and our current results, the role of PCLO in MDD, if present, is unlikely to be very large.…”

“…The third most significant single nucleotide polymorphism (SNP, rs2522833) coded for a non-synonymous amino acid change (p.Ser4814Ala) in the C2A domain of Piccolo. The association with MDD was independently reproduced by others (Hek et al, 2010;Aragam et al, 2011;Woudstra et al, 2012Woudstra et al, , 2013Verbeek et al, 2013), although it was not replicated in the more recent and largest GWAS to date (Ripke et al, 2013). A recent replicate case-control study (Minelli et al, 2012) investigated depression-related personality traits in healthy subjects as a function of the PCLO rs2522833 genotype.…”

Systems Approach to Identify Common Genes and Pathways Associated with Response to Selective Serotonin Reuptake Inhibitors and Major Depression Risk

“…Thus, it is hypothesized that dysfunction of ionotropic and metabotropic receptors are associated with the depressed phenotype. However, in a resequencing study, none of the GRM7 variants had shown the significance level with MDD in the Dutch cohort [118].…”

Multi-Trait GWAS and New Candidate Genes Annotation for Growth Curve Parameters in Brahman Cattle

“…Other methods to validate or refine the identified candidate genes in future studies can be done directly by a re-sequencing approach. The advent of next-generation sequencing (NGS), and the highly decreased whole-genome sequencing associated costs, allow us to sequence specific genome regions (related to genes of interest) of a few contrasting individuals and to access, for example, by alignment algorithms, causal polymorphisms underlying these regions[ 62 , 63 ].…”