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.

Ozomaro et al.

Ozomaro et al. BMC Medicine 2013 11:132   doi:10.1186/1741-7015-11-132

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