Table 2.
Psychiatric disease susceptibilities
| Gene(s) | Variant(s) | Population(s) | EPI | EF | BM | Key findings | Outcome | Ref. |
|---|---|---|---|---|---|---|---|---|
|
Major depressive disorder | ||||||||
|
5-HTT |
5-HTTLPR and EF: stressful life events |
Caucasian |
|
+ |
|
Homozygous or heterozygous carriers of the short allele had higher frequency of depression and suicidality when exposed to stressful life events. |
SIG |
[221] |
|
5-HTT |
STin2.9 |
Caucasian |
|
|
|
Increased frequency in MDD relative to controls |
SIG |
[7] |
|
5-HTT |
5-HTTLPR |
Caucasian |
|
|
|
Increased frequency in MDD relative to controls |
SIG |
[8] |
|
TPH1 |
microsatellite at 11p15.3-p14 |
Caucasian community-based sibships |
|
|
|
Association with MDD susceptibility and microsatellite |
SIG |
[11] |
|
TPH1 |
Various |
Caucasian |
|
|
|
Six haplotypes associated with MDD risk |
SIG |
[12] |
|
TPH2 |
rs120074175 (p.R441H) |
Caucasian (90%), AA (8%), East Asian (2%) |
|
|
|
Higher frequency of SNPs in patients with MDD compared with controls or patients with BP |
SIG |
[15] |
|
TPH2 |
rs120074175 (p.R441H) |
Caucasian (84%), Hispanic (6%), East Asian (5%), AA (3%), others (2%) |
|
|
|
SNP not identified in non-treatment-resistant and treatment-resistant patients with MDD, or in treatment-resistant patients with BP, or in controls |
NS |
[16] |
|
TPH2 |
rs120074175 (p.R441H), rs1843809 (c.608 + 5263G>T) |
Caucasian |
|
|
|
Higher frequency of SNPs in MDD relative to controls |
SIG |
[13] |
|
TPH2 |
Various |
East Asian (Korean) |
|
|
|
No association of the SNPs rs4570625, rs10748185, rs11179027, rs4469933, or rs17110747 in MDD, BP, or SZ |
NS |
[17] |
|
TPH2 |
rs4570625 (c.-141-703G>T), rs17110747 (c.*479G>A) |
Meta-analysis |
|
|
|
SNPs associated with MDD susceptibility by fixed-effects modeling; rs4570625 remained significant using random-effects calculations |
SIG |
[9] |
|
TPH2 |
rs4570625-rs10748185 (G>A). |
East Asian (Korean) inpatients |
|
|
|
Haplotype significantly associated with higher MADRS endpoints in MDD |
SIG |
[19] |
|
FKBP5 |
rs3800373 (c.*1136G>T)-(CC) rs1360780 (c.106-2636A>G) |
Post-mortem brain samples, ethnicity not specified |
|
|
|
Five clinical groups were compared: MDD, MDD + psychosis, MDD + HIV, HIV-positive, and HIV-negative. Genotype frequencies in the MDD and the MDD + psychosis groups differed from published allelic frequencies |
SIG |
[25] |
|
FKBP5 |
rs1360780 (c.106-2636A>G) |
Caucasian inpatients with MDD, BD, or dysthymia |
|
|
|
Carriers of the TT genotype experienced more depressive episodes, by a factor of 2:1 compared with the CC or CT genotypes |
SIG |
[24] |
|
FKBP5 |
rs1360780 (c.106-2636A>G) (TT), rs3800373 (GG) |
Caucasian treatment-resistant adolescents |
|
|
|
Genotypes were associated with suicidal events |
SIG |
[26] |
|
FKBP5 |
rs9470080, rs9394309, rs7748266, rs1360780; BM: reduced daytime cortisol secretion |
Caucasian older people |
|
|
+ |
Minor alleles were associated with decreased daytime cortisol levels and increased likelihood of depressive symptoms |
SIG |
[279] |
|
FKBP5 |
rs9470080 (c.-19-35815A>G), rs9296158 (c.509-1901T>C) and EF: prolonged stress exposure |
East Asian (Korean) |
|
+ |
|
Two SNPs were associated with anxiety and depression after prolonged stress in patients with cancer patients |
SIG |
[280] |
|
CRHR1 |
rs110402 (GG), rs242924 (GG); and EF: childhood trauma; and BM: response to DEX/CRH test |
Healthy Caucasians with history of early life stress |
|
+ |
+ |
In adults who had experienced maltreatment, the GG genotypes were associated with increased cortisol response to DEX/CRH test |
SIG |
[219] |
|
CRHR1 |
rs10473984 EF: childhood trauma |
|
|
+ |
|
SNP works synergistically with childhood trauma to increase risk of MDD |
SIG |
|
|
CRHR1 |
rs110402 (c.34-4338G>A); EF: childhood abuse; and BM: cortisol response to DEX/CRH test |
1: AA, 2: ethnically diverse |
|
+ |
+ |
In adult men who had experienced child abuse, the A allele was associated with reduced MDD symptoms and reduced cortisol response to DEX/CRH test |
SIG |
[220] |
|
CRHR1 |
rs110402 (c.34-4338G>A), rs7209436 (c.33 + 8207C>T) and rs7209436-rs110402-rs242924 (TAT); EF: childhood abuse |
AA, Caucasian |
|
+ |
|
Rare alleles were protective in a dose-dependent manner against MDD in the presence of child abuse |
SIG |
[217] |
|
CRHR1 |
rs7209436-rs110402-rs242924 (TAT); EF: childhood abuse |
Caucasian (>90%) |
|
+ |
|
TAT haplotype was protective against MDD in women exposed to severe maltreatment, but not in a replication study using different measure of trauma |
SIG |
[218] |
|
CRHR1 |
rs242939 (c.241 + 1631C>T), three haplotypes |
East Asian (Chinese) |
|
|
|
Allele and genotype association with MDD |
SIG |
[32] |
|
CRHR1 |
rs110402 (c.34-4348G>A) |
Caucasian |
|
|
|
Association between SNP and early onset of MDD and increased risk for a seasonal pattern |
SIG |
[33] |
|
CRHPB |
Haplotype block |
Caucasian (Swedish) |
|
|
|
In patients with recurrent MDD, haplotype block (s02-TT and s11-TT and s14-T) was significantly associated with disease compared with controls |
SIG |
[35] |
|
CRHPB |
Haplotype block |
Caucasian (Swedish and Belgian) |
|
|
|
Could not replicate findings of [35] in an extended Swedish or Belgian sample. Found higher frequency of haplotype block (s02-TT, s11-TT and s12C) in Swedish men compared with control men |
NS |
[36] |
|
HTR3A |
42 (CC); EF: early life stress (ELS); BM: frontolimbic gray-matter alterations |
Healthy Caucasian |
|
+ |
+ |
Genotype + ELS was a predictor of depressed mood. Carriers had greater frontolimbic gray-matter alterations, which were increased by ELS |
SIG |
[379] |
|
SYNE1 |
rs9371601 (c.1653 + 2159C>A) |
Caucasian |
|
|
|
Higher frequency of SNPs in recurrent MDD relative to controls |
SIG |
[52] |
|
NR3C1 |
EPI: NR3C1 promoter site methylation; and EF: history of childhood abuse |
Suicide victims |
+ |
+ |
|
In abused victims, NR3C1 promoter methylation was increased and glucocorticoid receptor mRNA reduced compared with non-abused victims or controls |
SIG |
[144] |
| -- |
BM: CSF concentration of CRF |
Various |
|
|
+ |
Increased CSF concentration of CRF is a replicable finding in MDD. Also seen in suicide victims |
SIG |
[28-31] |
| -- |
EF: birth trauma |
Monozygotic twins discordant for MDD |
|
+ |
|
Increased occurrence of birth trauma in SZ-affected twin |
SIG |
[223] |
| -- |
EF: obstetric complications, e.g. abnormal fetal growth/development, pregnancy and delivery complications |
Meta-analysis of population-based prospective studies |
|
+ |
|
Obstetric complications increased risk for SZ |
SIG |
[224] |
| -- |
BM: CSF concentration of norepinephrine metabolite MHPG |
Caucasian (81%) with MDD (85%) or BD (15%) |
|
|
+ |
Lower levels of MHPG were predictive of suicidal behavior, and correlated with higher medical lethality of suicide attempt |
SIG |
[190] |
| -- |
rs1360780 (c.106-2636A>G) |
Caucasian, Black |
|
|
|
Association of SNP with MDD risk in Caucasian sample |
SIG |
[34] |
|
Bipolar disorder | ||||||||
|
FKBP5 |
rs4713902 (c.-19-3406A>G), rs7757037 (c.841-238C>A), rs9296158 (c.509-1901T>C), rs3800373 (c.*1136G>T), rs9380525 (c.-19-22418C>G) |
Family trios and quads with BD-I, or BD-II + rMDD, or SZA-BD |
|
|
|
SNPs associated with BD in populations studied (BD-I, BD-II + rMDD, SZA/BD); rs4713902 remained significant after correction for multiple testing |
SIG |
[40] |
|
FKBP5 |
various |
Caucasian (Ashkenazi Jewish) |
|
|
|
No significant SNP or haplotype associations with BD or SZ identified |
NS |
[41] |
|
FKBP5 |
rs4713916 (c.20 + 18122T>C), rs1360780 (c.106-2636A>G), rs380037 |
Caucasian |
|
|
|
No significant association between SNPs and BD |
NS |
[42] |
|
ARNTL |
rs7107287 (c.-208 + 13499G>T), rs895682 (c.-135 + 13626T>C), rs1481892 (c.-208 + 2451G>C), rs4757142 (c.-207-5839G>A) |
Caucasian family trios |
|
|
|
SNPs rs7107287 and rs895682 showed significant transmission bias in family samples. In Pittsburg sample, genotype distribution of SNPs rs1481892, rs7107287 and rs4757142 differed from that of controls |
SIG |
[48] |
|
TIMELESS |
rs2279665 (c.114G>C), rs2291738 (c.2726-4A>G), rs774026 (c.1578 + 22T>C), rs2291739 (p.P1018L) |
Caucasian family trios |
|
|
|
SNPs (rs2279665, 2291738) showed transmission bias in family samples. Haplotype over-transmission involving SNPs rs2279665, rs774026, rs2291738, and rs2291739 |
SIG |
[48] |
|
CLOCK |
rs534654 (c.793-485A>G), rs6850524 (c.-289-5765G>C), rs4340844 (c.559 + 996T>G) |
Family trios and quads |
|
|
|
Suggestive evidence for transmission disequilibrium |
SUG |
[46] |
|
SYNE1 |
rs9371601 (c.1653 + 2159C>A) |
Caucasian |
|
|
|
Higher frequency of SNP in BD compared with controls |
SIG |
[52] |
|
COMT |
EPI: MB-COMT promoter methylation |
Post-mortem brain samples (97% Caucasian) |
+ |
|
|
Reduced methylation of COMT promoter in BD compared with controls led to higher MB-COMT expression in BD compared with controls |
SIG |
|
|
COMT |
EPI: MB-COMT promoter methylation |
Caucasian post-mortem brain samples |
+ |
|
|
Promoter methylation did not differ between BD and control brains |
NS |
[151] |
| -- |
EF: obstetric complications |
Meta-analysis |
|
+ |
|
No findings to suggest higher risk for BD relative to MDD or controls after exposure to obstetric complications |
NS |
[225] |
| -- |
BM: peripheral blood levels of BDNF |
Meta-analysis |
|
|
+ |
Relative to controls, patients with BD in manic or depressed states had reduced serum and plasma BDNF levels |
SIG |
[197] |
| -- |
BM: serum or plasma levels of BDNF |
Meta-analysis |
|
|
+ |
Relative to controls, patients with BD in manic or depressed states had reduced serum and plasma BDNF levels |
SIG |
[196] |
|
Schizophrenia | ||||||||
| GWAS |
various |
GWAS of MGS sample (Caucasian, AA) |
|
|
|
No significant finding in MGS case–control sample GWAS |
NS |
[58] |
| MHC region on chr6 |
rs3130375 (7kb from NOTCH4) and large sets of nominally associated ‘score alleles’ |
Caucasian, AA |
|
|
|
Imputed SNP rs3130375 reached genome-wide significance. Strong suggestion for a polygenic basis for SZ |
SIG |
[95,96] |
| MHC region on chr6 |
various |
Meta-analysis of MGS, ISC, and SGENE data |
|
|
|
Association between SZ and region of LD on chromosome 6p22.1 |
SIG |
[58] |
| MHC region on chr6 |
HIST1H2BJ: rs6913660, PRSS16: rs13219354, rs6932590, PGBD1: rs13211507 (c.642 + 2432T>C), NOTCH4: rs3131296 (c.2866-827A>G) |
GWAS of SGENE-plus, ISC, and MGS (Caucasian) |
|
|
|
With combined samples, MHC region SNPs showed genome-wide significance |
SIG |
[59] |
|
COMT |
rs165688 (p.V158M) |
Caucasian with velocardiofacial syndrome (VCFS) ± SZ |
|
|
|
No correlation between allelic distribution and SZ in individuals with VCFS |
NS |
[105,380] |
|
COMT |
rs165599 (c.*522G>A), rs737865 (c.-92 + 701A>G), rs165688 (p.V158M) |
Caucasian (Ashkenazi Jewish) |
|
|
|
G allele in the SNPs was associated with SZ. Haplotype rs737865-rs165599 (G-G) had most significant overall association with SZ |
SIG |
[106] |
|
COMT |
rs737865 (c.-92 + 701A>G) |
Meta-analysis (Caucasian) |
|
|
|
Nominally significant association between SNP and SZ in analyses restricted to European samples |
SIG |
[82] |
|
DISC1 |
t(1:11)(q43,q21) |
Caucasian (Scottish pedigree) |
|
|
|
Translocation found to be in significant LD with SZ |
SIG |
[107,108] |
|
DISC1 |
rs821616 (p.S704C), rs821597 (c.2042 + 7630G>A), rs7546310 (c.1982-32754A>C) BM: hippocampal structure and function |
Caucasian, replication: family trios (Caucasian and AA) |
|
|
+ |
704-Ser associated with altered hippocampal structure and formation in healthy subjects. Association between 704-Ser and SZ. Three-SNP haplotype associated with SZ in the family sample |
SIG |
[112] |
|
DISC2 |
n.9481C>T, n.11085C>A, n.11160G>A, n.11870T>C, n.11859T>C |
Caucasian (Scottish) |
|
|
|
No co-segregation with SZ or BD or significant association was detected. SNPs were not in LD |
NS |
[132] |
|
COMT |
EPI: Membrane-bound COMT (MB-COMT) promoter methylation |
Caucasian post-mortem brain samples |
+ |
|
|
COMT promoter methylation did not differ between SZ and control brains |
NS |
[151] |
|
COMT |
MB-COMT promoter EPI: COMT methylation. |
Post-mortem brain samples (97% Caucasian) |
+ |
|
|
Reduced methylation of COMT promoter in SZ compared with controls, resulting in increased MB-COMT expression in SZ compared with controls |
SIG |
[148] |
|
ZNF804A |
rs1344706 (c.256-19902A>C) |
GWAS: Caucasian (English); replication: Caucasian and East Asian (BUL, GRM, US, AUS, JPN, CHN, and ISR) |
|
|
|
Nominally significant association between SNP and SZ in samples; genome-wide association when case sample extended to include BD |
SIG |
[60] |
|
ZNF804A |
rs1344706 (c.256-19902A>C), rs7597593 (c.111 + 69783T>C), rs17508595 (c.111 + 19311C>G) |
Caucasian (Irish) |
|
|
|
Nominally significant association between SNPs and SZ + poor-outcome schizoaffective disorder |
SIG |
[61] |
|
ZNF804A |
rs12477914 and rs1366840 as surrogates for rs1344706 (c.256-19902A>C) |
Initial study: Caucasian; follow-up: Caucasian + CHN |
|
|
|
Nominally significant association between SNPs and SZ. When stratified by population, significant in 2 (RUS and DNK) of 13 (HUN, NOR, RUS, SWE, FIN, DEU, DNK, GBR, SCO, ISL, NLD, ITA, CHN) ethnic groups |
SIG |
[62] |
|
ZNF804A |
rs1344706 (c.256-19902A>C) |
East Asian (Han Chinese) |
|
|
|
Nominally significant association between SNP and SZ in a population-based sample. In a family-based trio study, trend toward significant over-transmission |
SIG/SUG |
[63] |
|
TCF4 |
rs9960767 (c.146-23634T>G) |
Caucasian (BEL, DNK, DEU, IRL, ITA, FIN, SPA, UK, USA) |
|
|
|
Association between the C allele and SZ in GWAS and in replication studies |
SIG |
[59,69] |
|
TCF4 |
rs2958182 (c.146-17653T>A) (as surrogate for rs9960767) |
East Asian (Han Chinese) |
|
|
|
SNP substituted for rs9960767 as rs9960767 is not polymorphic in CHN, is in LD with rs9960767, and is significantly associated with SZ in CHN |
SIG |
[71] |
|
TCF4 |
rs12966547 (g.542881G>A) |
Caucasian |
|
|
|
Significant association between SNP and SZ |
SIG |
[70] |
|
NRG1 |
HapICE (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, SNP8NRG243177 and SNP8NRG433E1006, & microsatellite repeats 478B14-848 and 420M9-1395) |
Caucasian |
|
|
|
Haplotype significantly associated with SZ, with a relative risk of 2.2 |
SIG |
[77] |
|
RELN |
EPI: RELN promoter methylation |
Post-mortem brain samples |
+ |
|
|
Increased methylation of RELN promoter in SZ compared with controls, leading to reduced RELN mRNA expression |
SIG |
[150] |
|
RELN |
EPI: RELN promoter methylation |
Post-mortem brain samples |
+ |
|
|
By contrast to [150], neither SZ nor control samples found promoter hypermethylation |
NS |
[152] |
|
HTR2A |
EPI: cytosine methylation at rs6313 (c.102>T) |
Post-mortem brain samples |
+ |
|
|
102C carriers have reduced 5HT2A gene expression. In SZ, there is a greater reduction in carriers than in non-SZ carriers. Antipsychotics that reduce CpG methylation lead to increased HTR2A expression |
SIG |
rev. in [153] |
|
TPH2 |
rs4570625 (c.-141-703G>T) rs4570625- rs4565946 ((c.-141-703G>T)-(c.255 + 1256C>T) (G-C)) |
Caucasian |
|
|
|
Higher frequency of SNP in patients with MDD compared with controls in discovery sample; not replicated in replication sample. Trend for rs4570625-rs4565946 G-C haplotype |
SUG |
[18] |
|
KCNH2 |
rs1036145 (c.76 + 496G>A) |
NIMH and CATIE cohorts |
|
|
|
Carriers of rs1036145-TT genotype showed greater change on the PANSS than carriers of TC and CC genotypes. rs1036145-TT and rs3800779-TT showed significant improvement in positive symptoms compared with TC/CC genotypes |
SIG |
[332] |
| -- |
EF: prenatal exposure to influenza (determined by ecologic data only) |
Caucasian (Finnish) |
|
+ |
|
Exposure to influenza during second and third trimesters increased risk of hospitalization for SZ |
SUG |
[226] |
| -- |
EF: prenatal exposure to influenza (determined by ecologic data only) |
Caucasian (English, Welsh) |
|
+ |
|
Number of births with subsequent SZ development was higher during influenza epidemic relative to corresponding time during non-epidemic years |
SUG |
[227] |
| -- |
EF: prenatal exposure to influenza (serologically documented) |
Caucasian, AA, Others (Native American, MEX, East Asian) |
|
+ |
|
Early to mid-gestational exposure to influenza increased risk for SZ |
SIG |
[228] |
| -- |
EF: prenatal exposure to influenza |
Meta-analysis |
|
+ |
|
No association between exposure and SZ identified |
NS |
[229] |
| -- | EF: prenatal exposure to maternal stress (wars, spousal demise, disasters, etc.) | Meta-analysis | + | Data show no effect of prenatal stress on risk for SZ | NS | [230] | ||
5-HTTLPR, 5-hydroxytryptophan transporter-linked polymorphic region; AA, African-American; AU, Australian; BD, bipolar disorder; BD-I, BD-II bipolar disorder types I and II; BDNF, brain-derived neurotrophic factor; BEL, Belgian; BGR, Bulgarian; BM: biomarkers; CATIE, Clinical Antipsychotic Trials of Intervention Effectiveness; CHN, Chinese; CRF, corticotropin-releasing factor; CSF, cerebrospinal fluid; DEX/CRH, Dexamethasone/corticotropin-releasing hormone; DNK, Danish; EF, environmental factors, ELS, early life stress; EPI, epigenetic factors; FIN, Finnish; GRM, German; GWAS, GWAS, Genome-wide association studies; HIV, human immunodeficiency virus; ISL, Icelandic; IRL, Irish; ISC, International Schizophrenia Consortium; ITA, Italian; ISR, Israeli; JPN, Japanese; KOR, Korean; LD, linkage disequilibrium; MB-COMT, membrane-bound catechol-O-methyltransferase; MDD, major depressive disorder; MEX, Mexican; MHPG, 3-methoxy-4-hydroxyphenylglycol;NIMH, National Institute of Mental Health; NLD, Dutch (Netherlands); NS, not significant; rMDD, recurrent MDD; RUS, Russian; SCO, Scottish; SGENE, Schizophrenia Genetics Consortium; SIG, significant; SNP, single-nucleotide polymorphism; SPA, Spanish; SUG, suggestive; SZ, schizophrenia; SZA-BD, schizoaffective disorder, manic or bipolar type; UK, United Kingdom; USA, American; VCFS, velocardiofacial syndrome.