Table 1.
Summary of Genetic Studies Investigating TRD
| Gene | Polymorphisms | Sample Size | Main Findings | Reference |
|---|---|---|---|---|
| Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) | rs1805502 | 178 TRD, 612 non-TRD, 779 HC | Increased risk of TRD in rs1805502 G allele carriers. | (Zhang et al., 2014) |
| Glutamate ionotropic receptor kainate type subunit 4 (GRIK4) | rs11218030, rs1954787 | 380 TRD, 247 non-TRD | Increased risk of TRD and psychotic symptoms during depressive episodes in rs11218030 G allele and rs1954787 GG genotype. | (Milanesi et al., 2015) |
| 100 TRD | Increased risk of non-response after ECT in rs11218030 G allele and rs1954787 GG genotype. | (Minelli et al., 2016) | ||
| Brain derived neurotrophic factor (BDNF) | rs6265 (Val66Met) | 62 TRD | Better response to ketamine in G (Val) allele. | (Laje et al., 2012) |
| 71 TRD | No association with ketamine response. | (Su et al., 2017) | ||
| 36 TRD | Better response to rTMS in G (Val) allele. | (Bocchio-Chiavetto et al., 2008) | ||
| BDNF, neurotrophic receptor tyrosine kinase 2 (NTRK2) | rs6265 (BDNF), rs1387923, rs2769605 and rs1565445 (NTRK2) | 644 non-TRD, 304 TRD | rs1565445 T allele, rs1565445 TT genotype, rs1565445 and rs1387923 T-T haplotype were associated with TRD. A genotypic combination at four loci in NTRK2 and BDNF (rs1387923-rs1565445- rs2769605-rs6265) was associated with TRD. | (Li et al., 2013) |
| CAMP responsive element binding protein 1 (CREB1) | rs2709376, rs2253206, rs7569963, rs7594560, rs4675690 | 119 non-TRD, 71 TRD | rs7569963 A allele, rs2253206-rs7569963 A-A and rs7569963-rs4675690 A-C haplotypes were associated with TRD. Negative results for the other SNPs. | (Serretti et al., 2011) |
| s889895, rs6740584, rs2551922, rs2254137 | 265 non-TRD, 102 TRD | No association was found for TRD. rs889895 GG was associated with remission. | (Calati et al., 2013) | |
| 147 non-TRD, 73 TRD | No association was found for TRD. rs2254137 AA was associated with remission. | (Fabbri et al., 2017) | ||
| Solute carrier family 6 member 4 (SLC6A4 or serotonin transporter) | 5-HTTLPR | 36 TRD | Better response to rTMS in LL genotype. | (Bocchio-Chiavetto et al., 2008) |
| 5-HTTLPR, rs25531 | 310 TRD, 284 HC | L(A)L(A) homozygote haplotype was more common in HC compared with TRD patients. | (Bonvicini et al., 2010) | |
| SLC6A4, solute carrier family 6 member 2 (SLC6A2 or norepinephrine transporter) |
5-HTTLPR (SLC6A4), rs2242446 (SLC6A2) | 119 TRD, 395 HC | 5-HTTLPR L/L in conjunction with SLC6A2 rs2242446 TT was less frequent in TRD patients compared with HC and in ECT non-responders compared with responders. | (Kautto et al., 2015) |
| Potassium two pore domain channel subfamily K member 2 (KCNK2) | rs12031300, rs10779646, rs17546779, rs12136349, rs2841616, rs7538655, rs2841608, rs7549184, rs10494996 | 264 non-TRD, 487 TRD | rs2841616, rs2841608, rs12136349, rs10494996 were associated with TRD in the whole cohort and in Caucasian patients. | (Perlis et al., 2008) |
| Protein phosphatase 3 catalytic subunit gamma (PPP3CC) | rs7430, rs10108011, rs11780915, rs2249098 | 276 non-TRD, 102 TRD | rs7430 and rs10108011 were associated with TRD. | (Fabbri et al., 2014) |
| PPP3CC | rs7430, rs10108011, rs11780915, rs2249098 | 147 non-TRD, 73 TRD | No association between genotypes and TRD. | (Fabbri et al., 2017) |
| PPP3CC, BDNF, 5-hydroxytryptamine receptor 2A (HTR2A or serotonin receptor 2A) | rs7430, rs10108011 (PPP3CC), rs6265, rs11030101, rs11030104, rs12273363 (BDNF), rs643627, rs6313 (HTR2A) | 76 non-TRD, 149 TRD | Using machine learning and clustering algorithms, a combination of 3 SNPs (rs7430 in PPP3CC, rs6265 in BDNF, rs6313 in HTR2A) and the clinical feature melancholia showed the best predictive performance of TRD. | (Kautzky et al., 2015) |
| HTR2A | rs643627, rs17288723, rs6313 | 276 non-TRD, 102 TRD | No association between these variants and TRD. | (Fabbri et al., 2014) |
| Catechol-O-methyltransferase (COMT) | rs4680 (Val108/158Met) | 100 TRD, 100 HC | The alternative allele A (Met) was more frequent in TRD than in HC and it was associated with worse ECT response. | (Lin et al., 2015) |
| 104 TRD | The A (Met) allele was associated with worse ECT response particularly regarding the core symptoms of depression and sleep-related symptoms. | (Domschke et al., 2010) | ||
| 90 TRD | No association between this variant and TMS response. | (Malaguti et al., 2011) | ||
| rs4680, rs174696 | 276 non-TRD, 102 TRD | No association between these variants and TRD. | (Fabbri et al., 2014) | |
| 5-hydroxytryptamine receptor 1A (HTR1A or serotonin receptor 1A) | rs6265 | 90 TRD | CC genotype was associated with higher symptom improvement after treatment with TMS. | (Malaguti et al., 2011) |
| HTR1A, BDNF | rs6295 (HTR1A), rs6265 (BDNF) | 119 TRD, 392 HC | The combination of rs6295 (HTR1A) GG and rs6265 (BDNF) GA + AA genotypes was more frequent in TRD compared with HC. | (Anttila et al., 2007) |
| Poly(A) binding protein cytoplasmic 4 like (PABPC4L) | GWAS (CNVs) with pathway analysis | 811 non-TRD, 452 TRD | A modest enrichment of duplications and a particular deletion spanning PABPC4L in TRD, but these findings were not significant after multiple- testing correction. Pathways regulating actin cytoskeleton were nominally associated with TRD. | (O’Dushlaine et al., 2014) |
| Calcium voltage-gated channel subunit alpha1 C (CACNA1C) (GO:0006942) | Pathway analysis in GWAS | 226 non-TRD, 394 TRD | The Gene Ontology term GO:0006942, including the CACNA1C gene, predicted the risk of TRD with a mean sensitivity of 0.83, specificity of 0.56, positive predictive value=0.77, negative predictive value=0.65 after cross-validation. | (Fabbri et al., 2018) |
| / | GWAS | 7795 non-TRD, 1311 TRD | No genome-wide significant finding. | (Li et al., 2016) |
Abbreviations: CNV,copy number variations; ECT,electroconvulsive therapy; HC,healthy controls; rTMS,repetitive transcranial magnetic stimulation.
Only candidate genes investigated by at least 2 independent studies and/or with complementary evidence of association with TRD (e.g., gene expression studies, in vitro or in vivo models) were reported. The results of GWAS were also reported. For each gene the nonabbreviated name is reported correspondence to the first occurrence.