Does refining the phenotype improve replication rates? A review and replication of candidate gene studies on Major Depressive Disorder and Chronic Major Depressive Disorder

Abstract

Replication has been poor for previously reported candidate genes involved in Major Depressive Disorder (MDD). One possible reason is phenotypic and genetic heterogeneity. The present study replicated genetic associations with MDD as defined in DSM-IV and with a more narrowly defined MDD subtype with a chronic and severe course. We first conducted a systematic review of genetic association studies on MDD published between September 2007 and June 2012 to identify all reported candidate genes. Genetic associations were then tested for all identified single nucleotide polymorphisms (SNPs) and the entire genes using data from the GAIN genome-wide association study (MDD: n = 1,352; chronic MDD subsample: n = 225; controls: n = 1,649). The 1,000 Genomes database was used as reference for imputation. From 157 studies identified inthe literature, 81 studies reported significant associations with MDD, involving 245 polymorphisms in 97 candidate genes, from which we were able to investigate 185 SNPs in 89 genes. We replicated nine candidate SNPs in eight genes for MDD and six in five genes for chronic MDD. However, these were not more than expected by chance. At gene level, we replicated 18 genes for MDD and 17 genes for chronic MDD, both significantly more than expected by chance. We showed that replication rates were improved for MDD compared to a previous, highly similar, replication study based on studies published before 2007. Effect sizes of the SNPs and replication rates of the candidate genes were improved in the chronic subsample compared to the full sample. Nonetheless, replication rates were still poor.

Genome‐wide gene‐environment interaction in depression: A systematic evaluation of candidate genes

“…Since the literature on candidate genes for MDD and GxE interaction in MDD is very broad, we focused on papers that reviewed the previous work in the field. The candidate list comprises SNPs/genes that were taken from two major reviews (Mandelli and Serretti, 2013 for GxE interaction in MDD; Luo et al, 2016 for candidate genes/SNPs in MDD). These candidates cover genes from central monoaminergic systems such as serotonin, dopamine or noradrenalin, from the glutamatergic system, corticotrophin system, neurotropic system or from inflammatory processes (e.g.…”

Co‐shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome

“…Several candidate genes and GWAS studies have been performed to identify risk genes, but often these studies used admixed populations. At least 97 candidate genes have been reported showing risk variants for MDD, but replication efforts have not consistently been successful, perhaps due to the role of environmental factors; they have been more successful in selected subsamples, highlighting the necessity to better ascertain the phenotype and study homogenous family datasets (Luo et al, ). Recently, a low‐coverage whole‐genome sequencing in a case–control study of Han Chinese women with recurrent MDD identified two genome‐wide significant loci, one near sirtuin 1 ( SIRT1 ), and the other in the phospholysine phosphohistidine inorganic pyrophosphate phosphatase ( LHPP ) gene; both loci were replicated in an independent Chinese sample, and highly significant in the discovery and replication joint analysis (consortium, ).…”

Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder

“…The heritability of MDD is estimated to be around 30-40% [9,10], indicating that genetic factors have a pivotal role in MDD. Though great effort has been made to investigate the genetic underpinnings of MDD, only limited risk variants and genes have been identified by genetic linkage and association studies [11][12][13][14][15]. The advent of GWAS provides an opportunity to explore the genetic basis of MDD.…”