Aug 20, 20231 min read

Kamilla PR Models Sets 1121

Before the availability of GWAS, common variation studies of MDD were largely limited to biological candidate genes in neurotransmitter, neuropeptide, and neuroendocrine systems related to antidepressant targets or implicated in animal models. The results of these studies have been mixed and most have been underpowered to detect the modest effects expected for common variants. Meta-analyses of biological candidate gene studies have provided some support for association between MDD and specific variants (Gatt et al, 2015). In particular, nominal associations have been reported in meta-analyses for variants in several serotonergic genes (HTR2A, SLC6A4 HTR1A,TPH2) (Gao et al, 2012; Kishi et al, 2013; Lopez-Leon et al, 2007; Zhao et al, 2014), as well as APOE, DRD4, GNB3, SLC6A3, and MTHFR (Clarke et al, 2010; Lopez-Leon et al, 2007; Wu et al, 2013). Of note, however, none of these genes has been implicated in large GWAS (Wray et al, 2012). As Flint and Kendler (2014) have demonstrated, candidate gene meta-analyses of MDD have been underpowered and the data thus far are consistent with a lack of significant findings in any meta-analysis. Using a different approach, Lee et al (2012) examined 188 MDD candidate genes and 178 biological gene sets related to these genes in a pathway analysis encompassing three GWAS data sets. Genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD after correction for multiple testing.