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Table 2 Psychiatric disease susceptibilities

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

 

+

 

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]

  1. 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.