Journal of Anxiety Disorders 28 (2014) 873–883

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Journal of Anxiety Disorders

Review

Progress towards understanding the genetics of posttraumatic stress disorder Joanne Voisey ∗ , Ross McD. Young, Bruce R. Lawford, Charles P. Morris Institute of Health and Biomedical Innovation, Queensland University of Technology, 2 George St., Brisbane 4000, QLD, Australia

a r t i c l e

i n f o

Article history: Received 14 July 2014 Accepted 16 September 2014 Available online 5 October 2014 Keywords: Anxiety Genetics PTSD Epigenetics Trauma

a b s t r a c t Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene–environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder. Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heritability of PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic risk and signalling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene by environment (GxE) interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics of treatment response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)(American Psychiatric Association, 2013) posttraumatic stress disorder (PTSD) is no longer classified as an anxiety disorder but is categorised in disorders relating to traumatic and stressful events (Friedman, 2013). Some of the symptoms of PTSD are characteristic but there are some that overlap with other psychiatric disorders (Schnurr, 2013). The trauma can cause significant changes in the hypothalamic pituitary adrenal axis (HPA) (Yehuda, 2001) determining future responses to

∗ Corresponding author. Tel.: +61 7 31386261; fax: +61 7 31386030. E-mail address: [email protected] (J. Voisey). http://dx.doi.org/10.1016/j.janxdis.2014.09.014 0887-6185/Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.

873 874 874 878 878 878 880 880

stress. PTSD can lead to profound social dysfunction as memories from the traumatic event can result in fear responses that mimic the original exposure. Those with PTSD can experience sleep difficulties, are easily frightened and have concentration and memory problems (Brunello et al., 2001). As a result sufferers may experience relationship challenges, substance misuse and experience feelings of isolation, hopelessness and anger. PTSD can result from a variety of traumatic events including military combat, violet assaults, physical and sexual abuse, terrorist encounters, natural disasters and serious accidents. Females are twice as likely to develop PTSD compared to males (Breslau, 2009; Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995). However, most individuals that are exposed to a life threatening experience will not develop PTSD (Breslau, 2009) and this is largely thought to be determined by genetics. This review will focus on epigenetics and the genetic

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and environmental risk factors of PTSD as well as the genetics of treatment response. 2. Heritability of PTSD Twin studies of Vietnam veterans have confirmed that genetic vulnerability is associated with PTSD (Koenen et al., 2002; Lyons et al., 1993; True et al., 1993). Approximately 30% of the variance in liability for PTSD symptoms (including re-experiencing, avoidance and hyper-arousal) was found to be genetic after analysing phenotypes of monozygotic and dizygotic twins (Koenen et al., 2002; Lyons et al., 1993; True et al., 1993). A recent twin study suggests that heritable influences account for 46% of the variance in PTSD (Sartor et al., 2012) but this could be as high as 71% in females (Sartor et al., 2011). Full pedigrees for PTSD have not been collected as genetic vulnerability to PTSD can only be assessed if a traumatic experience has occurred. However, some studies of family history have shed light on familial susceptibility to PTSD. One of the first was a study of World War One veterans with “psycho-neurosis” who were compared with controls that had a physical injury as a result of war. None of the controls reported a family history of “psychoneurosis” compared to 75% of the cases (Wolfsohn, 1918). 3. Genetic risk and signalling pathways There have been numerous genetic association studies examining the role of various genes in PTSD and these are summarised in Table 1. The table lists 68 candidate gene studies covering 31 genes that examined association between PTSD or a PTSD-related phenotype and numerous polymorphisms. It also lists six genome wide association studies (GWAS) that identified four genes associated with PTSD. Table 1 list studies that detected association as well as those that failed to detect association, although it is likely that many negative studies have not been published. The earliest study in 1991 (Comings et al., 1991) examined the rs1800497 single nucleotide polymorphism (SNP), also known as TaqIA. This SNP was originally considered to be in the dopamine D2 receptor (DRD2) gene as it is only 10 kilobases downstream but it was later discovered that it lies in a tyrosine kinase gene known as the ankyrin repeat and kinase domain containing 1 gene ANKK1 (Dubertret et al., 2004). However, it has been postulated that the involvement of TaqIA in psychiatric disorders is due to its proximity to, and regulatory effect on the DRD2 gene (Swagell et al., 2012). Between 1991 and 2004 there was a total of six PTSD association studies, four of which involved the TaqIA or other DRD2 SNPs (Table 1). Since that time there has been increased activity in this area, particularly in the last few years. There have been a total of eight studies examining DRD2/TaqIA SNPs (Table 1). Because of the role of dopamine in stress biology, it is not surprising that dopamine-regulating genes including DRD2 have been found to be associated with PTSD (Comings, Muhleman, & Gysin, 1996; Lawford et al., 2003; Voisey et al., 2009) although the case for TaqIA is less convincing. A pair of polymorphisms in the promoter of the serotonin transporter gene (SLC6A4) have also been implicated in PTSD risk and produce a low expression allele (Lee et al., 2005). This involved a SCL6A4 variable number of tandem repeats polymorphism (VNTR) in the promoter region (referred to in Table 1 as 5 -VNTR) with short (14 repeats) and long (16 repeats) alleles and a modifying SCL6A4 A/G polymorphism (rs25531). Only the long repeat allele that also contains the rs25531 A allele results in high levels of SCL6A4 expression while all short alleles and long alleles combined with the rs25531 G allele result in low levels of SCL6A4 expression. Table 1 lists 17 association studies of the SLC6A4 promoter polymorphisms, some of which only examined the 5 -VNTR polymorphism. The majority of these studies detected

association with the SLC6A4 polymorphisms (14 studies detected association and three did not). Despite this, a recent meta analysis of 13 studies showed that there is no support for a direct effect of SLC6A4 polymorphisms in PTSD (Navarro-Mateu, Escamez, Koenen, Alonso, & Sanchez-Meca, 2013). More recently, a nonsynonymous polymorphism in brain–derived neurotrophic factor (BDNF) was found associated with psychotic symptoms in PTSD (Pivac et al., 2012) and fear conditioning (Felmingham, DobsonStone, Schofield, Quirk, & Bryant, 2013; Soliman et al., 2010). Identifying genes that modulate the actions of glucocorticoids including stress and cognition may identify novel SNPs associated with PTSD. The NOS1AP gene encodes nitric oxide synthase 1 adaptor protein that binds to the signalling molecule, neuronal nitric oxide synthase (nNOS). Nitric oxide (NO) is produced from its precursor l-arginine by the enzyme NO synthase (NOS) which includes at least three distinct isoforms—neuronal (nNOS), endothelial, and inducible NOS. Studies have found that NO release is involved in the activation of glutamate N-methyl-d-aspartate (NMDA) receptors (Southam & Garthwaite, 1993). NOS1AP competes with postsynaptic density protein-95 (PSD-95) for nNOS binding and is thought to reduce NMDA receptor signalling via PSD-95 and nNOS. An earlier study that identified NOS1AP found that overexpression of NOS1AP results in a loss of PSD95/nNOS complexes in transfected cells (Jaffrey, Snowman, Eliasson, Cohen, & Snyder, 1998). The NO cascade has also been shown to be responsible for hippocampal shrinkage. Cognitive defects evident from PTSD are thought to be the result of hippocampal degeneration (Elzinga & Bremner, 2002). During stress, glutamate is released via increased sensitivity of hippocampal glucocorticoid receptors which in turn increase the risk of hippocampus atrophy (Sapolsky, 2001). Rat studies have found stress mediated glucocorticoid release activated NOS activity which subsequently down-regulated hippocampal NMDA receptors and total gamma-aminobutyric acid (GABA) levels (Harvey, Oosthuizen, Brand, Wegener, & Stein, 2004). A partial agonist of the NMDA receptor, d-cycloserine, has proved successful in the treatment of PTSD (Heresco-Levy et al., 2002). A SNP, rs386261, in NOS1AP has recently been found associated with PTSD in Vietnam War veterans (Lawford et al., 2013). The study also found that the GG genotype was associated with increased severity of depression in patients with PTSD which may increase suicide risk and indicate a comorbid phenotype. This study and many of the studies listed in Table 1 should be viewed with caution until they have been replicated, as they are the first reports of association in the genes studied. Although PTSD is seen as an anxiety disorder, it is frequently comorbid with depression and studies have identified genes common to both (Koenen et al., 2008; Lawford, Young, Noble, Kann, & Ritchie, 2006). As much as 58% of the genetic variance in PTSD could be attributed to heritable influences shared with major depressive disorder (Koenen et al., 2008). A study of Vietnam veterans also found that PTSD risk was higher in individuals that had a family history of depression (True et al., 1993) suggesting that PTSD and depression share common genetic liability. Table 1 highlights some of the difficulties faced when conducting genetic association studies in PTSD. Generally speaking the size of the cohorts of PTSD cases and controls is quite small and the type of trauma to which many of the PTSD cases were exposed was either poorly defined or of a varied nature. It is well recognised that there is more power to detect genetic association when the phenotype of the cases is more severe and more uniform. It is therefore recommended that future studies concentrate on PTSD patients who present with profound impairments following exposure to a relatively uniform trauma such as a specific natural disaster or a particular military conflict. Genome-wide association studies (GWAS) are commonly used to identify genetic associations in case/control studies of disease.

J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883

875

Table 1 Genetic association studies examining association between PTSD or a PTSD-related phenotype. Gene

Finding

Study reference

Trauma

Candidate gene studies rs1800497 ANKK1

T associated

Severe combat

ANKK1

rs1800497

T associated

ANKK1 DRD2 DRD2

rs1800497 rs1079597 rs1800498 rs1800497

No association No association No association T associated

Comings et al. (1991) Comings et al. (1996) Gelernter et al. (1999)

DRD2

rs1800497 rs6277 rs1799732 rs12364283

No association C associated No association G associated

ANKK1 BDNF SLC6A4

rs1800497/rs6265 5 -VNTR

DRD4

VNTR exon3

Val/A1 associated no association L-allele associated

ANKK1 SLC6A3

rs1800497 rs28363170 rs28363170 rs6265 5 -VNTR

ANKK1 ANKK1 DRD2 DRD2

SLC6A3 BDNF SLC6A4

Polymorphism

SLC6A3

rs28363170

SLC6A3

rs28363170

SLC6A3

rs28363170

SLC6A3

rs28363170/rs27072

SLC6A4

5 -VNTR

SLC6A4



5 -VNTR/rs25531 

SLC6A4

5 -VNTR/rs25531

SLC6A4

5 -VNTR

SLC6A4

5 -VNTR 

No association No association 9 Rept associated No association No association 9 Rept associated 9 Rept associated

9 Rept associated Haplotype associated

S-allele associated S+-haplotype associated L/A haplotype associated S-allele associated S-allele associated S+-haplotype associated S-allele associated 12 rept associated L/L associated

SLC6A4

5 -VNTR/rs25531

SLC6A4

5 -VNTR Intron2 VNTR

SLC6A4

5 -VNTR

SLC6A4

5 -VNTR/rs25531

S+ haplotype associated

SLC6A4

5 -VNTR/rs25531

S+ haplotype associated

SLC6A4

5 -VNTR/rs25531

SLC6A4

5 -VNTR/rs25531

S+ haplotype associated S+ haplotype associated

SLC6A4 TPH2

5 -VNTR/rs25531/ rs4570625 5 -VNTR rs2108977 rs11178997

SLC6A4 THP1 TPH2

S + T+ genotype associated S associated T associated

Control numbers

Controls exposed

Ethnicity

35

314

No

USA Eur

Combat

37

19

Yes

USA Eur

Combat

52

87

No

USA Eur

Young et al. (2002) Voisey et al. (2009)

Combat

91

51

No

Aus Eur

Combat

127

228

NS

Aus Eur

Nelson et al. (2014)a Hemmings et al. (2013)

Various

651

1098

NS

Aus mixed

TB exposure

150

NA

Yes

Dragan and Oniszczenko (2009) Bailey et al. (2010) Valente et al. (2011b)

Flood

24

83

Yes

South Africa non-Eur Poland

Spitak earthquake Urban violence

200

NA

Yes

65

369

NS

Segman et al. (2002) Drury, Theall, Keats, and Scheeringa (2009) Chang et al. (2012) Drury, Brett, Henry, and Scheeringa (2013)b Lee et al. (2005)

Various

102

104

Yes

Israel

Kilpatrick et al. (2007) Grabe et al. (2009) Koenen et al. (2009a) Kolassa et al. (2010a) Wang et al. (2011) Sayin et al. (2010) Thakur, Joober, and Brunet (2009)c Xie et al. (2009)d Walsh, Uddin, Soliven, Wildman, and Bradley (2014) Wald et al. (2013) Pietrzak, Galea, Southwick, and Gelernter (2013) Hermann et al. (2012) Goenjian et al. (2012)

Case numbers

Armenia Eur Brazil mixed

Hurricane Katrina New Orleans

88

88

Yes

USA AA & other

Various

62

258

Yes

Various

66

77

Yes

USA AA & other USA AA & other

Various

100

197

NS

Korean

Hurricane Katrina Florida Various

19

570

Yes

USA mixed

67

2978

NS

Hurricanes Florida various 2004 Rwandan genocide Combat

19

571

Yes

German Eur USA mixed

331

77

Yes

Rwandan

51

48

Yes

Physical trauma stroke

29

48

Yes

USA Eur & other Turkey Eur

Major vehicle accidents

24

17

Yes

USA Eur

Various trauma or childhood adversity Various

229

1023

Yes

USA Eur & AA

205

477

Yes

USA AA

Various

487

NA

Yes

Hurricane Ike

149

NA

Yes

Israel mixed Jews USA Eur & other

74

NA

NA

200

NA

Yes

Fear conditioning Spitak earthquake

Not specified Armenia Eur

876

J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883

Table 1 (Continued) Gene

Polymorphism

Finding

Study reference

Trauma

SLC6A4 HTR2A

no association G associated GG associated in females

55

Various

ADCYAP1R1 & ADCYAP1

rs2267735 43 Tag-SNPs

ADCYAP1R1

rs2267735

ADCYAP1R1

rs2267735

ADCYAP1R1

rs2267735

ADCYAP1R1

rs2267735

BDNF BDNF BDNF

rs6265 rs6265 G712A C270 T rs6265

C associated, females no association C associated, females C associated, females C associated, females C associated, females No association no association

Mellman et al. (2009) Lee, Kwak, Paik, Kang, and Lee (2007) Ressler et al. (2011)

Various

HTR2A

5 -VNTR/rs25531 rs6311 rs6311

BDNF

rs6265

A associated

BDNF

rs6265

A associated

APOE

rs7412 rs429358

T/T haplotype associated

APOE

rs7412 rs429358 rs7412 rs429358 rs806369/rs1049353 rs1049353 rs806377 rs6454674

T/T haplotype associated C/C haplotype associated Haplotypes associated A associated No association No association No association

APOE CNR1

CNR1

CNR1 FKBP5

FKBP5

FKBP5 COMT CHRNA5

rs806369 rs1049353 rs806377 rs6454674 rs2180619 rs1049353 rs9296158 rs3800373 rs1360780 rs9470080 rs992105 rs737054 rs1334894 rs4713916 rs9296158 rs3800373 rs1360780 rs9470080 rs9470080 rs4680 rs16969968

A associated

AA associated no association A associated C associated T associated T associated No association No association No association No association No association No association No association T associated T associated A associated A associated

COMT

rs4680

A associated

COMT

rs4680

no association

COMT

rs4680

A associated

PRKCA

rs4790904

A associated

PRKCA

rs4790904

G associated

Control numbers

Controls exposed

Ethnicity

63

Yes

107

161

NS

USA AA & Eur Korean

Various

398

839

Yes

USA AA & other

Almli et al. (2013) Uddin et al. (2013a) Wang et al. (2013) Stevens et al. (2014) Lee et al. (2006) Zhang et al. (2006) Soliman et al. (2010) Pivac et al. (2012) Felmingham et al. (2013) Freeman, Roca, Guggenheim, Kimbrell, and Griffinn (2005) Kim et al. (2013) Lyons et al. (2013) Lu et al. (2008)

Various

911

NA

Yes

USA AA

Various

23

378

Yes

Wenchuan earthquake Various

146

174

Yes

USA AA & other China

49

NA

Yes

Various Various

107 96

161 250

NS NS

72

NA

NA

370

206

Yes

not specified Croatian

55

NA

NA

Aus Eur

54

NA

NA

USA Eur

Fear conditioning Combat Fear conditioning Combat

Case numbers

USA AA females Korean USA Eur

Combat

128

128

Yes

Korean

Combat

39

131

Yes

ADHD parents

25

291

NS

USA Eur & others USA Eur

Lu et al. (2008)

Not specified

17

292

NS

Finland Eur

Heitland et al. (2012) Binder et al. (2008)

Fear conditioning Various

142

NA

NA

Netherlands

762

NA-

NA

USA AA & other

Xie et al. (2010)d

Various

343

2084

NS

USA Eur & AA

Boscarino, Erlich, Hoffman, Rukstalis, and Stewart (2011) Valente et al. (2011a) Kolassa, Kolassa, Ertl, Papassotiropoulos, and De Quervain (2010b) Schulz-Heik et al. (2011) de Quervain et al. (2012) Liu et al. (2013)

Various

502

NA

Yes

USA Eur

65

369

NS

340

84

Yes

Brazil mixed Rwandan

51

48

Yes

134

213

Yes

391

570

Yes

Urban violence Rwandan genocide

Combat Rwandan genocide Combat

USA Eur & other Rwandan USA Eur & AA

J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883

877

Table 1 (Continued) Gene

Polymorphism

Finding

Study reference

Trauma

Case numbers

Control numbers

Controls exposed

Ethnicity

ANK3

C associated T associated T associated G associated G associated No association

Logue et al. (2013b)e

Combat & partners

295

196

Yes

USA Eur

Duan et al. (2014)

Various

173

287

NS

Han Chinese

A associated C associated No association No association No association No association No association No association No association No association No association No association No association

White et al. (2013)

Hurricanes Florida various 2004

564

NA

Yes

USA Eur

DBH

rs9804190 rs1049862 rs28932171 rs11599164 rs17208576 rs208679 rs10836233 rs2300182 rs769217 rs7104301 rs7949972 rs12938031 rs479288 rs173365 rs17689966 rs242924 rs2664008 rs171441 rs16940686 rs242939 rs242936 rs7209436 rs11040 rs1611115

Combat

133

34

Yes

Croatian

DTNBP1

rs9370822

C associated

Combat

127

250

NS

Aus Eur

GABRA2

T associated A associated A associated No association No association

Various

46

213

NS

Not specified

KPNA3

rs279836 rs279826 rs279871 rs279858 rs2273816

Mustapic et al. (2007) Voisey et al. (2010) Nelson et al. (2009)f

Combat

121

237

NS

Aus Eur

NOS1AP

rs386231

A associated

Combat

121

237

NS

Aus Eur

NPY

rs16139

No association

Combat

77

202

NS

USA Eur

NR3C1

No association

Combat

118

42

Yes

Aus Eur

RGS2

rs6189 rs6190 rs56149945 rs4606

Morris et al. (2012) Lawford et al. (2013) Lappalainen et al. (2002) Bachmann et al. (2005)

C associated

Amstadter et al. (2009)

273

334

Yes

USA Eur & others

SRD5A2

rs523349

961

Yes

rs182455

146

174

Yes

rs10038727 rs4576167 & 113 tag-SNPs

Wenchuan earthquake African Conflicts

USA AA & other China

WWC1

Gillespie et al. (2013) Cao et al. (2013) Wilker et al. (2013)g

482

STMN1

C associated, males C associated, females G associated G associated

Hurricanes Florida Various 2004 Various

212

579

Yes

Rwandan Ugandan

Logue et al. (2013a) Amstadter et al. (2013) Guffanti et al. (2013) Xie et al. (2013)

Combat & partners Florida Hurricanes Various

295

196

Yes

USA Eur

551

NA

NA

USA Eur

318

NS

Various

Various

300

1278

NS

USA Eur & AA

Wolf et al. (2014) Solovieff et al. (2014)

Combat & partners Various

293

191

Yes

USA Eur

845

1693

Yes

USA Eur women

CAT

CRHR1

Genome-Wide Association Studies (GWAS) rs8042149 C associated RORA RORA

rs8042149

C associated

incRNA AC068718 intergenic SNP TLL1 TLL1

rs10170218

Associated

NA

rs406001 rs6812849 rs7691872 NA

SLC18A2

rs363276

Associated Associated Associated No significant SNPs SNP & haplotype associated

94

Where possible, studies are arranged by gene then chronologically. Abbreviations: AA, African American; Aus, Australia; Eur, European descent (excluding Hispanic descent for USA populations); NA, not applicable; NS, unselected controls. a 1430 SNPs were analysed in 72 candidate genes. b Double heterozygotes excluded from analysis. c Did not achieve significance, p = 0.052. d Cases and controls were recruited from a cohort of cocaine or opioid dependence and non-dependent controls. e 359 ANK3 SNPs were examined. f Cases and controls were recruited from a cohort with nicotine dependence. g This study is listed as a candidate gene study but GWAS data was generated then ‘mined’ for WWC1 Tag-SNP data.

878

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There have been several papers describing recommendations for PTSD GWAS studies (Cornelis, Nugent, Amstadter, & Koenen, 2010; Koenen et al., 2009c; Koenen, Duncan, Liberzon, & Ressler, 2013) but it is only in the past couple of years that GWAS studies have been conducted in PTSD (Table 1). The first study, like most using the GWAS approach, looked at a very large number of SNPs (greater than 1.2 million). However, most GWAS studies need to analyse data from a very large number of cases and controls (typically thousands to tens of thousands) in order to achieve statistical significance. This study is limited by examining less than 300 cases and less than 200 controls (Logue et al., 2013a). Despite this limitation they detected association with the retinoid-related orphan receptor alpha (RORA) locus and PTSD in trauma exposed veterans (Logue et al., 2013a). RORA has a role in protecting brain cells from injury, stress and disease (Logue et al., 2013a) and the association with RORA has since been replicated in hurricane exposed adults with traumatic stress symptoms (Amstadter et al., 2013). The number of PTSD cases reported in the six GWAS studies listed in Table 1 varied between 94 (Guffanti et al., 2013) and 551 (Amstadter et al., 2013) which is far less than the number usually required in GWAS studies due to the difficulty achieving significant associations with smaller numbers of cases and controls. The second GWAS study was performed in a relatively small female African American population (94 PTSD cases and 319 controls) who had been exposed to varying traumatic events (Guffanti et al., 2013). Only one SNP (rs10170218) in a novel RNA gene incRNA AC068718.1 reached genome-wide significance. This SNP association was replicated in a female European population (578 PTSD cases and 1963 controls) and found to be marginally significant. Another study performed a GWAS in 300 European Americans and 444 African Americans with PTSD (Xie et al., 2013). Only one SNP, rs406001, in an intergenic region of DNA devoid of known genes reached genome wide significance in the European American population and no SNPs reached genome significance in the African American sample set. Even though no tolloid-like 1 gene (TLL1) SNPs achieved GWAS significance, when six TLL1 SNPs were examined in an independent European American sample, two showed association with PTSD (Xie et al., 2013). The TLL1 gene encodes a metalloprotease that is essential for the formation of the interventricular septum in mouse heart (Clark et al., 1999). It is notable that none of the GWAS studies detected association in any of the genes identified in the candidate gene studies (Table 1). Often there is also no plausible biological link between the associated SNP and PTSD, e.g. one study (Xie et al., 2013) found association with a SNP in an intergenic region more than 600 kilobases from the nearest gene, named COBL, that is the human homologue of a mouse gene known as cordon-bleu.

4. Gene by environment (GxE) interactions Gene by environment (GxE) interactions can determine if an individual is more likely to have resilience or later develop PTSD as a consequence of traumatic exposure. Repeated stress during childhood can cause disruptive HPA (hypothalamic-pituitaryadrenal-axis) response to future stress (Davidson & McEwen, 2012; Feder, Nestler, & Charney, 2009). Child abuse is known to increase the risk of PTSD (Brewin, Andrews, & Valentine, 2000; Paolucci, Genuis, & Violato, 2001). One of the first studies to determine the effects of genetics in response to environmental risk was a longitudinal study that tested why stressful events lead to depression in some individuals but not others (Caspi et al., 2003). Caspi et al. (2003) identified a polymorphism in the promoter region of the serotonin transporter (SLC6A4) gene that moderates the influence of stressful life events and childhood maltreatment on depression. This same polymorphism was later found associated with PTSD

risk in individuals that had a history of childhood adversity (Xie, Kranzler, Farrer, & Gelernter, 2012; Xie et al., 2009). Four SNPs of the FKBP5 gene have also been shown to interact with severity of child abuse as a predictor of adult PTSD symptoms (Binder et al., 2008). Importantly, these FKBP5 SNPs alone were not associated with PTSD indicating a true gene–environment interaction. Gamma-aminobutyric acid receptor alpha-2 (GABRA2) variants are also associated with increased lifetime PTSD after exposure to childhood trauma (Nelson et al., 2009). Other GxE research has utilised data from the 2004 Florida hurricanes. The first study analysed variation in the promoter of the serotonin transporter gene (SLC6A4). Individuals with high hurricane exposure who carried the low expression promoter variant and had low social support were 4.5 times more likely to develop PTSD compared to low-risk individuals (Kilpatrick et al., 2007). A second study by the same group examined whether features of the social environment (county-level crime rate and unemployment) modified the association of the SLC6A4 promoter variant and risk of current PTSD in a sample from the 2004 Florida Hurricane Study. Individuals carrying the low expressing allele were at increased risk for PTSD in high stress environment conditions (Koenen et al., 2009a). The third study analysing the Florida hurricane data focused on a gene previously found to be associated with anxiety, the regulator of G-protein signalling 2 gene (RGS2). The rs4606 polymorphism of RGS2 was associated with increased symptoms of PTSD under high hurricane exposure and low social support. It was also associated with lifetime PTSD symptoms under conditions of lifetime exposure to a potentially traumatic event, and low social support (Amstadter et al., 2009). Although GxE studies have the potential to identify risk and resilience to PTSD as discussed in a recent review of GxE interactions in PTSD, previous studies have been limited because of the large number of possible candidate genes and environmental variables which are often documented by retrospective self-reports (Koenen, Amstadter, & Nugent, 2009b). This review concluded that longitudinal studies need to be designed with comprehensive and objective measures of risk (Koenen et al., 2009b).

5. Epigenetics The heritability of PTSD is between 30% and 46% (Koenen et al., 2002; Sartor et al., 2012; True et al., 1993), yet the trigger for PTSD is due to environmental effects. The definition of epigenetics has changed over time, and now generally refers to the heritable, but modifiable, regulation of genetic functions that are not mediated through the DNA sequence, in particular DNA methylation and histone modification. Early epigenetic studies focused on cancer. There is a growing body of evidence to suggest epigenetics plays an important role in psychiatric disorders as well (McGowan & Szyf, 2010; Toyokawa, Uddin, Koenen, & Galea, 2012). Stress is one of the major environmental factors that triggers epigenetic change. There have been few whole genome studies in humans demonstrating epigenetic contribution to PTSD onset. Instead there have been focused epigenetic studies looking at methylation in targeted genes (eight studies to date) and only four genome-wide methylation studies of PTSD in humans (Mehta et al., 2013; Smith et al., 2011; Uddin et al., 2010, 2013b). Table 2 summarises these studies. The most recent whole genome methylation array study was performed in peripheral blood cells where they identified unique biological modifications in adults with PTSD in the presence of exposure to childhood abuse (Mehta et al., 2013). The second study analysed blood samples from 23 PTSD patients who had experienced various traumatic events and 77 individuals without PTSD across 14,000 genes (Uddin et al., 2010). Among the

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Table 2 Summary of PTSD epigenetic studies. Study

Method

Genes analysed

Sample

Outcomes

Uddin et al. (2010)

Illumina Human Methylation27 BeadChip

Genome-wide

Koenen et al. (2011)

Illumina Human Methylation27 BeadChip

SLC6A4

23 PTSD, 77controls Mixed ethnicity Different Trauma Types (DTT) 23 PTSD, 77controls Mixed ethnicity DTT

Ressler et al. (2011)

Illumina Human Methylation27 BeadChip

PAC1

Smith et al. (2011)

Illumina Human Methylation27 BeadChip

Genome-wide

Genes implicated in immunity differentially methylated in PTSD SLC6A4 methylation levels modified the effect of the number of traumatic events on PTSD CpG methylation level of PAC1 was associated with PTSD diagnosis 5 genes TPR, CLEC9A, APC5, ANXA2 and TLR8 differentially methylated in PTSD

Uddin et al. (2011)

Illumina Human Methylation27 BeadChip

33 genes previously found associated with PTSD

Chang et al. (2012)

Illumina Human Methylation27 BeadChip

SLC6A3

Rusiecki et al. (2012)

Pyrosequencing

LINE-1 and Alu

Klengel et al. (2013)

Pyrosequencing

FKBP5

Mehta et al. (2013)

Illumina Human Methylation 450k array

Genome-wide

Norrholm et al. (2013)

Illumina Human Methylation27 BeadChip

COMT

Rusiecki et al. (2013)

Pyrosequencing

IGF2, H19, IL8, IL16, IL18

Uddin et al. (2013b)

Illumina Human Methylation27 BeadChip

Genome-wide

Yehuda et al. (2013)

Methylation mapping using clones

NR3C1, FKBP5

Yehuda et al. (2014b)

Methylation mapping using clones Methylation mapping using clones

NR3C1

Sequenom epityper

NR3C1

pyrosequencing

NR3C1

Yehuda et al. (2014a)

Labonte, Azoulay, Yerko, Turecki, and Brunet (2014) Perroud et al. (2014)

NR3C1

N = 107 Mixed ethnicity DTT 25 PTSD + childhood trauma (ct), 25 PTSD no ct,26 controls + ct, 34 controls no ct African-American 23 PTSD, 77controls Mixed ethnicity DTT 16 PTSD, 67 controls. Mixed ethnicity DTT US military deployed to Afghanistan or Iraq. 75 PTSD, 75 controls Mixed ethnicity 30 PTSD with ct, 45 no ct and PTSD Mixed ethnicity but majority (72) African–American 32 PTSD with ct, 29 PTSD with no ct, 108 controls Mixed ethnicity 98 PTSD 172 controls Mixed ethnicity DTT US military deployed to Afghanistan or Iraq. 75 PTSD, 75 controls Mixed ethnicity N = 100 trauma exposed sample with low socioeconomic position assessed as a modifier. Ethnicity mixed but predominantly of African-American DTT N = 16 Mixed ethnicity 8 combat veterans treated with psychotherapy (responders0 and with PTSD who were non-responders to psychotherapy N = 122 combat veterans Mixed ethnicity Adult offspring with a Holocaust survivor parent N = 80 and participants without parental Holocaust exposure or PTSD N = 30 PTSD N = 16 non-PTSD Mixed ethnicity DTT N = 25 women exposed to Tutsi genocide during pregnancy and their children and N = 25 women pregnant during the same period but not exposed to genocide and their children. Tutsi ethnicity

All the above studies were performed in peripheral blood. Studies are listed chronologically. DTT = different trauma types.

MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD 3’UTR VNTR of the SLC6A3 gene s associated with PTSD risk and high methylation status in the SLC6A3 promoter Hypermethylation of LINE-1 in controls post-deployment and of Alu in cases post-deployment FKBP5 DNA demethylation mediates gene–childhood trauma interactions Childhood maltreatment associated with distinct epigenetic profiles in PTSD Higher methylation of COMT promoter associated with impaired fear inhibition Controls lower methylation levels of H19 and IL18 post-deployment. Cases increased methylation levels of IL18 post-deployment genes predominantly related to nervous system function

FKBP5 associated with symptom severity.

Lower NR3C1 promoter methylation NR3C1 promoter methylation altered in relation to parental PTSD

Lower methylation of NR3C1 promoter Exposed mothers and their children had higher methylation of NR3C1 exon IF.

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genes found to be differentially methylated, there was an overrepresentation of those involved in immune system function which were found to be under methylated in PTSD patients. Using CMV-a as an independent biological marker of immune response to infection it was found that this latent herpes virus had significantly higher activity in patients with PTSD. These results suggest that a traumatic event can alter immune function by altering methylation levels of immune related genes. A later study by the same group investigated socioeconomic position as a modifier of the association between methylation and traumatic stress (Uddin et al., 2013b). Like their earlier study they identified genes pertaining to nervous system function. The third genome wide methylation study analysed global and site-specific methylation across 14,000 genes (Smith et al., 2011). The study involved African-American participants who had a diagnosis of PTSD with (n = 25) or without (n = 25) childhood trauma and controls with (n = 26) or without (n = 34) childhood trauma. Global methylation was increased in those with PTSD and five genes implicated in inflammation were found to be differentially methylated in PSTD subjects. The majority of PTSD methylation studies to date have been limited in that they have analysed mixed ethnic groups and used peripheral tissue rather than a functional tissue such as brain. Only one study (Smith et al., 2011) analysed an African-American cohort as a defined ethnic group. All other studies have used mixed ethnic groups in their analysis but the majority of samples (>75%) used in these groups are African-American. The only studies to use a predominantly Caucasian population were the two studies (Rusiecki et al., 2012, 2013) that analysed United States military personnel deployed to Afghanistan or Iraq. The majority of individual studies have also collected participants with varying trauma types that may influence methylation patterns. More recently there have been two focused studies of the glucocorticoid receptor gene (NR3C1) that have analysed defined ethnic groups and trauma (Perroud et al., 2014; Yehuda et al., 2014a). These studies have analysed relatively small samples sizes but are more likely to produce consistent and reliably results with well defined cohorts.

6. Genetics of treatment response Fear is one of the most basic human responses that enables us to respond appropriately to emotionally or physically threatening situations (Mineka & Oehlberg, 2008). However, in an appropriate fear response it is just as important to extinguish the fear response when the ‘threat’ is removed (Hofmann, 2008). The persistence of a fear response is thought to be the basis of anxiety disorders such as PTSD (Myers & Davis, 2002). Drug therapy for PTSD is relatively ineffective (Shalev et al., 2012) and there are few pharmaceuticals that have been developed specifically for PTSD. One of the most favoured current treatment strategies is cognitive behaviour therapy which is directed to counteracting the fear response by repeated exposure to the fear stimulus without its negative consequences (Felmingham et al., 2013; Myers & Davis, 2002). There have been very few studies looking at the genetics of treatment response in anxiety disorders like PTSD. Consequently, to date, only three candidate genes have emerged; brain derived neurotrophic factor (BDNF) (Felmingham et al., 2013), the endogenous human cannabinoid receptor 1 (CNR1) (Heitland et al., 2012) and the SCL6A4 promoter polymorphic region (Hermann et al., 2012). A recent study on of the BDNF Val66Met polymorphism (rs6265) revealed poorer response to exposure therapy in the PTSD patients who carried the Met-66 allele of BDNF compared with patients who were homozygous for the Val66 allele (Felmingham et al., 2013). This is particularly important, as recent animal and human evidence suggests that BDNF is critical in facilitating fear extinction

(Felmingham et al., 2013; Soliman et al., 2010) which is a key component of exposure therapy. Hermann et al. (2012) looked at the combined effect of three polymorphisms on fear acquisition and extinction. They studied two SCL6A4 polymorphisms (the 5 -VNTR and rs25531) that produce a low expression allele. They also combined these polymorphisms with another SNP (rs4570625, G/T) in the tryptophan hydroxylase-2 (TPH2) gene that appears to influence the rate of 5HT synthesis in the presynapse. It was shown that in carriers of the SCL6A4 short allele and the TPH2 rs4570625 T allele there was a profound effect on the acquisition and extinction of fear. Another study looked at the role of two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of the CNR1 gene in the genetics of fear extinction (Heitland et al., 2012). Neither polymorphism affected acquisition and expression of conditioned fear. Carriers of the rs2180619 G allele (GG and GA) displayed robust fear extinction but the A allele homozygotes (AA) showed an absence of fear extinction. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. This study suggested that the cannabinoid receptor 1 is a potential target for treatment by novel and existing agonists of the receptor. 7. Conclusions Understanding the molecular genetics of PSTD is still in the early stages. To date, candidate gene studies have been the major approach used to identify genetic association with PTSD and there have been a small number of very recent GWAS studies of limited sample size. Because of the large sample size required for a GWAS study and the limitations of obtaining an adequate sample size in a PTSD cohort, the candidate gene approach may prove the most useful. Future epigenetic studies that investigate the impact of environmental factors including stress on biological processes are likely to contribute to our understanding of PTSD susceptibility. More evidence suggests that individuals exposed to childhood maltreatment are more likely to be susceptible to PTSD as adults. Identifying when DNA methylation changes occur is also important in understanding the origins of PTSD. If gene–environmental factors can be identified that affect DNA methylation status, then the incidence of PTSD could possibly be reduced by targeting the environmental triggers. Recent technological advances, such as the advent of very large genome-wide epigenetics arrays, are likely to yield significant advances over the coming years. A more complete understanding of the molecular genetics of PTSD raises the prospect of improved early detection, stress avoidance of those at risk and improved treatment strategies, ultimately leading to improved outcomes for PTSD sufferers and reduced burden of disease for sufferers, their families and the community in general. References Almli, L. M., Mercer, K. B., Kerley, K., Feng, H., Bradley, B., Conneely, K. N., et al. (2013). ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 162B, 262–272. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. Amstadter, A. B., Koenen, K. C., Ruggiero, K. J., Acierno, R., Galea, S., Kilpatrick, D. G., et al. (2009). Variant in RGS2 moderates posttraumatic stress symptoms following potentially traumatic event exposure. Journal of Anxiety Disorders, 23, 369–373. Amstadter, A. B., Sumner, J. A., Acierno, R., Ruggiero, K. J., Koenen, K. C., Kilpatrick, D. G., et al. (2013). Support for association of RORA variant and post traumatic stress symptoms in a population-based study of hurricane exposed adults. Molecular Psychiatry, 18, 1148–1149. Bachmann, A. W., Sedgley, T. L., Jackson, R. V., Gibson, J. N., Young, R. M., & Torpy, D. J. (2005). Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology, 30, 297–306.

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