Table 3.
Functional roles for candidate risk genes for major depressive disorder (MDD).
| Risk gene (Variant) for MDD | Locus | # of cases/controls | Odds ratio (OR) | Functional associations |
|---|---|---|---|---|
| MTHFR (rs1801133) | 1p36.22 |
1241/11,021 1280 / 10,429 875 / 3859 |
OR = 1.36 (p = 0.003) [190] OR = 1.14 (p < 0.05) [191] OR = 1.2 (p < 0.05) [192] |
The C677T polymorphism is associated with migraine with aura in depressed patients [193]; The rs1801133 “CC” variant is associated with inattentiveness and hyperactivity-impulsivity [194]; T-allele carriers showed increased risk of depression following exposure to childhood trauma [195] |
| NEGR1 (rs1432639) | 1p31.1 | 135,458/344,901 | OR = 1.04 (p = 4.6E10-15) [31] | Negr1−/− mice showed anxiety- and depression-related behavior and decreased hippocampal neurogenesis [196]; other NEGR1 SNPs are linked to upregulation of NEGR1 in the PFC, cognition, and educational attainment [197] and with obesity [198] |
| DAT/SLC6A3 (VNTR 3-UTR) | 5p15.33 | 151 / 272 | OR = 2.06 (p < 0.05) [192] | Variants have been associated with attentional switching deficits [199]; altered time estimation [200] and perception [201]; and superior decoding of mental state valence [202] |
| HTR1A (rs6295) | 5q12.3 |
1,658 / 2,046 3,199 / 4,380 |
OR = 0.821 (p = 0.0327) [203] OR = 0.87 (p = 0.006) [204] |
rs6295 is associated with negative life events in MDD in young adults (age 20–29) [205] |
| DRD4 (48 bp ins/del) | 11p15.5 | 318 / 814 | OR = 1.73 (p = 0.003) [206] | SNPs are associated with sexually dimorphic effects on hypercompetitiveness, anxiety, and depression [207]; drug use frequency [208]; and negative emotionality at 3–36 months; [209] |
| GNB3 (rs5443) | 12p13.31 | 375/492 | OR = 1.38 (p < 0.05) [192] | Associated with SSRI-induced insomnia [210]; nortriptyline [211] and other antidepressant responses [212, 213] |
| OLFM4 (rs12552) | 13q14.3 | 135,458/344,901 | OR = 1.04 (p = 6.1E10-19) [31] | OLFM4 SNPs are associated with increased sedentary activity and increased body fat in 6-year-old children [214] |
| LRFN5 (rs4904738) | 14q21.1 | 135,458/344,901 | OR = 0.97 (p = 2.6E0-9) [31] | LRFN5 SNPs are associated with both MDD and chronic pain [215]; depression risk in older adults [216]; synapse formation and maintenance [217]; other 14q21.2 mutations associated with autism spectrum disorder and developmental delay [218, 219] |
| RBFOX1 (rs8063603, rs7198928) | 16p13.3 | 135,458/344,901 |
OR = 0.97 (p = 6.9E10-9) [31] OR = 1.03 (p = 1.0E10-8) [31] |
RBFOX1 mediates cell type-specific splicing in cortical interneurons [220] and variants are associated with brain glucose metabolism [221]; aggression [222]; and neuro- developmental disorders [223] |
| 5HTTLPR / SLC6A4 (44 bp ins/del) | 17q11.2 |
6836/14,903 275/739 3752/5707 |
OR = 1.09 (p = 0.007) [224] OR = 1.2 (p = 0.049) [225] OR = 1.11 (p < 0.05) [192] |
SNPs have been associated with altered brain synchrony in time perception [201]; decoding of positive and negative valence mental states [202]; increased susceptibility to MDD following negative life events in some cohorts [205] but not others [144]; negative emotionality at 3-36 months [209] |
Summary of previously reported functional roles for candidate risk genes for MDD from significant candidate gene meta-analysis studies (red) and from a genome-wide association (GWA) study (blue). Genome loci are indicated and genes are sorted by locus. Known functional associations for each candidate risk gene are described. The number of depressed cases and controls in each study is indicated. The strength of association between candidate risk gene and MDD is indicated by the odds ratio (OR, the odds of having the risk variant in the depressed case group divided by the odds of having the risk variant in the control group) and p-values indicating level of significance are indicated. This is not meant to be an exhaustive list of known candidate genes for MDD, but rather a representation of functional roles for hypothesized risk variants from GWA studies or meta-analyses. The genes from candidate gene studies are the genes found to have significance in at least one meta-analysis comprehensively reviewed by Ref. [32]. We also refer readers to the systematic review and meta-analysis of imaging genetics studies involving participants with MDD by ref. [126]. The four genes from a GWA study [31] were highlighted by the authors of the study that identified them. A more recent GWA study has identified 102 independent risk variants [33], some of which overlap with ref. [31]. Note that some functional associations were identified in smaller scale studies and may not have been replicated yet in larger samples.
bp base pairs, 3′-UTR 3′-untranslated region, del deletion, ins insertion, rs refSNP, SNP single nucleotide polymorphism, VNTR variable number tandem repeat.