From: Personalized medicine in psychiatry: problems and promises
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 | Â | + | Â | 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 | Â | Â | Â | Increased frequency in MDD relative to controls | SIG | [7] |
5-HTT | 5-HTTLPR | Caucasian | Â | Â | Â | Increased frequency in MDD relative to controls | SIG | [8] |
TPH1 | microsatellite at 11p15.3-p14 | Caucasian community-based sibships | Â | Â | Â | Association with MDD susceptibility and microsatellite | SIG | [11] |
TPH1 | Various | Caucasian | Â | Â | Â | Six haplotypes associated with MDD risk | SIG | [12] |
TPH2 | rs120074175 (p.R441H) | Caucasian (90%), AA (8%), East Asian (2%) | Â | Â | Â | 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%) | Â | Â | Â | 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 | Â | Â | Â | Higher frequency of SNPs in MDD relative to controls | SIG | [13] |
TPH2 | Various | East Asian (Korean) | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | Genotypes were associated with suicidal events | SIG | [26] |
FKBP5 | rs9470080, rs9394309, rs7748266, rs1360780; BM: reduced daytime cortisol secretion | Caucasian older people | Â | Â | + | 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) | Â | + | Â | 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 | Â | + | + | 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 | Â | Â | + | Â | SNP works synergistically with childhood trauma to increase risk of MDD | SIG | Â |
CRHR1 | rs110402 (c.34-4338G>A); EF: childhood abuse; and BM: cortisol response to DEX/CRH test | 1: AA, 2: ethnically diverse | Â | + | + | 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 | Â | + | Â | 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%) | Â | + | Â | 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) | Â | Â | Â | Allele and genotype association with MDD | SIG | [32] |
CRHR1 | rs110402 (c.34-4348G>A) | Caucasian | Â | Â | Â | Association between SNP and early onset of MDD and increased risk for a seasonal pattern | SIG | [33] |
CRHPB | Haplotype block | Caucasian (Swedish) | Â | Â | Â | 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) | Â | Â | Â | 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 | Â | + | + | 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 | Â | Â | Â | 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 | + | + | Â | 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 | Â | Â | + | Increased CSF concentration of CRF is a replicable finding in MDD. Also seen in suicide victims | SIG | |
-- | EF: birth trauma | Monozygotic twins discordant for MDD | Â | + | Â | 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 | Â | + | Â | Obstetric complications increased risk for SZ | SIG | [224] |
-- | BM: CSF concentration of norepinephrine metabolite MHPG | Caucasian (81%) with MDD (85%) or BD (15%) | Â | Â | + | 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 | Â | Â | Â | 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 | Â | Â | Â | 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) | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | Suggestive evidence for transmission disequilibrium | SUG | [46] |
SYNE1 | rs9371601 (c.1653 + 2159C>A) | Caucasian | Â | Â | Â | Higher frequency of SNP in BD compared with controls | SIG | [52] |
COMT | EPI: MB-COMT promoter methylation | Post-mortem brain samples (97% Caucasian) | + | Â | Â | Reduced methylation of COMT promoter in BD compared with controls led to higher MB-COMT expression in BD compared with controls | SIG | Â |
COMT | EPI: MB-COMT promoter methylation | Caucasian post-mortem brain samples | + | Â | Â | Promoter methylation did not differ between BD and control brains | NS | [151] |
-- | EF: obstetric complications | Meta-analysis | Â | + | Â | 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 | Â | Â | + | 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 | Â | Â | + | 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 | |
MHC region on chr6 | various | Meta-analysis of MGS, ISC, and SGENE data | Â | Â | Â | 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) | Â | Â | Â | 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 | |
COMT | rs165599 (c.*522G>A), rs737865 (c.-92 + 701A>G), rs165688 (p.V158M) | Caucasian (Ashkenazi Jewish) | Â | Â | Â | 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) | Â | Â | Â | Nominally significant association between SNP and SZ in analyses restricted to European samples | SIG | [82] |
DISC1 | t(1:11)(q43,q21) | Caucasian (Scottish pedigree) | Â | Â | Â | Translocation found to be in significant LD with SZ | SIG | |
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) | Â | Â | + | 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) | Â | Â | Â | 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 | + | Â | Â | 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) | + | Â | Â | 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) | Â | Â | Â | 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) | Â | Â | Â | 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 | Â | Â | Â | 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) | Â | Â | Â | 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) | Â | Â | Â | Association between the C allele and SZ in GWAS and in replication studies | SIG | |
TCF4 | rs2958182 (c.146-17653T>A) (as surrogate for rs9960767) | East Asian (Han Chinese) | Â | Â | Â | 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 | Â | Â | Â | Significant association between SNP and SZ | SIG | [70] |
NRG1 | HapICE (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, SNP8NRG243177 and SNP8NRG433E1006, & microsatellite repeats 478B14-848 and 420M9-1395) | Caucasian | Â | Â | Â | Haplotype significantly associated with SZ, with a relative risk of 2.2 | SIG | [77] |
RELN | EPI: RELN promoter methylation | Post-mortem brain samples | + | Â | Â | 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 | + | Â | Â | 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 | + | Â | Â | 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 | Â | Â | Â | 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 | Â | Â | Â | 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) | Â | + | Â | 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) | Â | + | Â | 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) | Â | + | Â | Early to mid-gestational exposure to influenza increased risk for SZ | SIG | [228] |
-- | EF: prenatal exposure to influenza | Meta-analysis | Â | + | Â | No association between exposure and SZ identified | NS | [229] |
-- | EF: prenatal exposure to maternal stress (wars, spousal demise, disasters, etc.) | Meta-analysis | Â | + | Â | Data show no effect of prenatal stress on risk for SZ | NS | [230] |