Journal of Anxiety Disorders 28 (2014) 873–883
Contents lists available at ScienceDirect
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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J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883
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.
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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.
J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883 Bailey, J. N., Goenjian, A. K., Noble, E. P., Walling, D. P., Ritchie, T., & Goenjian, H. A. (2010). PTSD and dopaminergic genes, DRD2 and DAT, in multigenerational families exposed to the Spitak earthquake. Psychiatry Research, 178, 507–510. Binder, E. B., Bradley, R. G., Liu, W., Epstein, M. P., Deveau, T. C., Mercer, K. B., et al. (2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. Journal of the American Medical Association, 299, 1291–1305. Boscarino, J. A., Erlich, P. M., Hoffman, S. N., Rukstalis, M., & Stewart, W. F. (2011). Association of FKBP5, COMT and CHRNA5 polymorphisms with PTSD among outpatients at risk for PTSD. Psychiatry Research, 188, 173–174. Breslau, N. (2009). The epidemiology of trauma, PTSD, and other posttrauma disorders. Trauma, Violence & Abuse, 10, 198–210. Brewin, C. R., Andrews, B., & Valentine, J. D. (2000). Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. Journal of Consulting and Clinical Psychology, 68, 748–766. Brunello, N., Davidson, J. R., Deahl, M., Kessler, R. C., Mendlewicz, J., Racagni, G., et al. (2001). Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment. Neuropsychobiology, 43, 150–162. Cao, C., Wang, L., Wang, R., Dong, C., Qing, Y., Zhang, X., & Zhang, J. (2013). Stathmin genotype is associated with reexperiencing symptoms of posttraumatic stress disorder in Chinese earthquake survivors. Progress in Neuro-psychopharmacology & Biological Psychiatry, 44, 296–300. Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389. Chang, S. C., Koenen, K. C., Galea, S., Aiello, A. E., Soliven, R., Wildman, D. E., & Uddin, M. (2012). Molecular variation at the SLC6A3 locus predicts lifetime risk of PTSD in the Detroit Neighborhood Health Study. PLoS One, 7, e39184. Clark, T. G., Conway, S. J., Scott, I. C., Labosky, P. A., Winnier, G., Bundy, J., et al. (1999). The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development, 126, 2631–2642. Comings, D. E., Comings, B. G., Muhleman, D., Dietz, G., Shahbahrami, B., Tast, D., et al. (1991). The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. Journal of the American Medical Association, 266, 1793–1800. Comings, D. E., Muhleman, D., & Gysin, R. (1996). Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Bioloigical Psychiatry, 40, 368–372. Cornelis, M. C., Nugent, N. R., Amstadter, A. B., & Koenen, K. C. (2010). Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Current Psychiatry Reports, 12, 313–326. Davidson, R. J., & McEwen, B. S. (2012). Social influences on neuroplasticity: stress and interventions to promote well-being. Nature Neuroscience, 15, 689–695. de Quervain, D. J., Kolassa, I. T., Ackermann, S., Aerni, A., Boesiger, P., Demougin, P., et al. (2012). PKCalpha is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors. Proceedings of the National Academy of Sciences of the United States of America, 109, 8746–8751. Dragan, W. L., & Oniszczenko, W. (2009). The association between dopamine D4 receptor exon III polymorphism and intensity of PTSD symptoms among flood survivors. Anxiety Stress Coping, 22, 483–495. Drury, S. S., Brett, Z. H., Henry, C., & Scheeringa, M. (2013). The association of a novel haplotype in the dopamine transporter with preschool age posttraumatic stress disorder. Journal of Child and Adolescent Psychopharmacology, 23, 236–243. Drury, S. S., Theall, K. P., Keats, B. J., & Scheeringa, M. (2009). The role of the dopamine transporter (DAT) in the development of PTSD in preschool children. Journal of Traumatic Stress, 22, 534–539. Duan, Z. X., Li, W., Kang, J. Y., Zhang, J. Y., Chen, K. J., Li, B. C., et al. (2014). Clinical relevance of tag single nucleotide polymorphisms within the CAT gene in patients with PTSD in the Chongqing Han population. International Journal of Clinical and Experimental Pathology, 7, 1724–1732. Dubertret, C., Gouya, L., Hanoun, N., Deybach, J. C., Ades, J., Hamon, M., et al. (2004). The 3’ region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. Schizophrenia Research, 67, 75–85. Elzinga, B. M., & Bremner, J. D. (2002). Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? Journal of Affective Disorders, 70, 1–17. Feder, A., Nestler, E. J., & Charney, D. S. (2009). Psychobiology and molecular genetics of resilience. Nature Reviews Neuroscience, 10, 446–457. Felmingham, K. L., Dobson-Stone, C., Schofield, P. R., Quirk, G. J., & Bryant, R. A. (2013). The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Bioloigical Psychiatry, 73, 1059–1063. Freeman, T., Roca, V., Guggenheim, F., Kimbrell, T., & Griffin, W. S. (2005). Neuropsychiatric associations of apolipoprotein E alleles in subjects with combat-related posttraumatic stress disorder. The Journal of Neuropsychiatry and Clinical Neurosciences, 17, 541–543. Friedman, M. J. (2013). Finalizing PTSD in DSM-5: getting here from there and where to go next. Journal of Traumatic Stress, 26, 5556–5648. Gelernter, J., Southwick, S., Goodson, S., Morgan, A., Nagy, L., & Charney, D. S. (1999). No association between D2 dopamine receptor (DRD2) A system alleles, or DRD2 haplotypes, and posttraumatic stress disorder. Bioloigical Psychiatry, 45, 620–625. Gillespie, C. F., Almli, L. M., Smith, A. K., Bradley, B., Kerley, K., Crain, D. F., et al. (2013). Sex dependent influence of a functional polymorphism in steroid
881
5-alpha-reductase type 2 (SRD5A2) on post-traumatic stress symptoms. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 162B, 283–292. Goenjian, A. K., Bailey, J. N., Walling, D. P., Steinberg, A. M., Schmidt, D., Dandekar, U., et al. (2012). Association of TPH1, TPH2, and 5HTTLPR with PTSD and depressive symptoms. Journal of Affective Disorders, 140, 244–252. Grabe, H. J., Spitzer, C., Schwahn, C., Marcinek, A., Frahnow, A., Barnow, S., et al. (2009). Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. The American Journal of Psychiatry, 166, 926–933. Guffanti, G., Galea, S., Yan, L., Roberts, A. L., Solovieff, N., Aiello, A. E., et al. (2013). Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women. Psychoneuroendocrinology, 38, 3029–3038. Harvey, B. H., Oosthuizen, F., Brand, L., Wegener, G., & Stein, D. J. (2004). Stressrestress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berlin), 175, 494–502. Heitland, I., Klumpers, F., Oosting, R. S., Evers, D. J., Leon Kenemans, J., & Baas, J. M. (2012). Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Translational Psychiatry, 2, e162. Hemmings, S. M., Martin, L. I., Klopper, M., van der Merwe, L., Aitken, L., de Wit, E., et al. (2013). BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. Progress in Neuro-psychopharmacology & Biological Psychiatry, 40, 273–280. Heresco-Levy, U., Kremer, I., Javitt, D. C., Goichman, R., Reshef, A., Blanaru, M., et al. (2002). Pilot-controlled trial of D-cycloserine for the treatment of posttraumatic stress disorder. The International Journal of Neuropsychopharmacology, 5, 301–307. Hermann, A., Kupper, Y., Schmitz, A., Walter, B., Vaitl, D., Hennig, J., et al. (2012). Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction. PLoS One, 7, e44352. Hofmann, S. G. (2008). Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clinical Psychology Review, 28, 199–210. Jaffrey, S. R., Snowman, A. M., Eliasson, M. J., Cohen, N. A., & Snyder, S. H. (1998). CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron, 20, 115–124. Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M., & Nelson, C. B. (1995). Posttraumatic stress disorder in the National Comorbidity Survey. Archives of General Psychiatry, 52, 1048–1060. Kilpatrick, D. G., Koenen, K. C., Ruggiero, K. J., Acierno, R., Galea, S., Resnick, H. S., et al. (2007). The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. The American Journal of Psychiatry, 164, 1693–1699. Kim, T. Y., Chung, H. G., Shin, H. S., Kim, S. J., Choi, J. H., Chung, M. Y., et al. (2013). Apolipoprotein E gene polymorphism, alcohol use, and their interactions in combat-related posttraumatic stress disorder. Depression and Anxiety, 30, 1194–1201. Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., et al. (2013). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature Neuroscience, 16, 33–41. Koenen, K. C., Aiello, A. E., Bakshis, E., Amstadter, A. B., Ruggiero, K. J., Acierno, R., et al. (2009). Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment. American Journal of Epidemiology, 169, 704–711. Koenen, K. C., Amstadter, A. B., & Nugent, N. R. (2009). Gene–environment interaction in posttraumatic stress disorder: an update. Journal of Traumatic Stress, 22, 416–426. Koenen, K. C., De Vivo, I., Rich-Edwards, J., Smoller, J. W., Wright, R. J., & Purcell, S. M. (2009). Protocol for investigating genetic determinants of posttraumatic stress disorder in women from the Nurses’ Health Study II. BMC Psychiatry, 9, 29. Koenen, K. C., Duncan, L. E., Liberzon, I., & Ressler, K. J. (2013). From candidate genes to genome-wide association: the challenges and promise of posttraumatic stress disorder genetic studies. Bioloigical Psychiatry, 74, 634–636. Koenen, K. C., Fu, Q. J., Ertel, K., Lyons, M. J., Eisen, S. A., True, W. R., et al. (2008). Common genetic liability to major depression and posttraumatic stress disorder in men. Journal of Affective Disorders, 105, 109–115. Koenen, K. C., Harley, R., Lyons, M. J., Wolfe, J., Simpson, J. C., Goldberg, J., et al. (2002). A twin registry study of familial and individual risk factors for trauma exposure and posttraumatic stress disorder. The Journal of Nervous and Mental Disease V 190, 209–218. Koenen, K. C., Uddin, M., Chang, S. C., Aiello, A. E., Wildman, D. E., Goldmann, E., et al. (2011). SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depression and Anxiety, 28, 639–647. Kolassa, I. T., Ertl, V., Eckart, C., Glockner, F., Kolassa, S., Papassotiropoulos, A., et al. (2010). Association study of trauma load and SLC6A4 promoter polymorphism in posttraumatic stress disorder: evidence from survivors of the Rwandan genocide. The Journal of Clinical Psychiatry, 71, 543–547. Kolassa, I. T., Kolassa, S., Ertl, V., Papassotiropoulos, A., & De Quervain, D. J. (2010). The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism. Bioloigical Psychiatry, 67, 304–308. Labonte, B., Azoulay, N., Yerko, V., Turecki, G., & Brunet, A. (2014). Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Translational Psychiatry, 4, e368.
882
J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883
Lappalainen, J., Kranzler, H. R., Malison, R., Price, L. H., Van Dyck, C., Rosenheck, R. A., et al. (2002). A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Archives of General Psychiatry, 59, 825–831. Lawford, B. R., Mc, D. Y. R., Noble, E. P., Kann, B., Arnold, L., Rowell, J., et al. (2003). D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder. European Neuropsychopharmacology, 13, 313–320. Lawford, B. R., Morris, C. P., Swagell, C. D., Hughes, I. P., Young, R. M., & Voisey, J. (2013). NOS1AP is associated with increased severity of PTSD and depression in untreated combat veterans. Journal of Affective Disorders, 147, 87–93. Lawford, B. R., Young, R., Noble, E. P., Kann, B., & Ritchie, T. (2006). The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. European Psychiatry, 21, 180–185. Lee, H. J., Kang, R. H., Lim, S. v., Paik, S. W., Choi, M. J., & Lee, M. S. (2006). No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and post-traumatic stress disorder. Stress Health, 22, 115–119. Lee, H. J., Kwak, S. K., Paik, J. W., Kang, R. H., & Lee, M. S. (2007). Association between serotonin 2A receptor gene polymorphism and posttraumatic stress disorder. Psychiatry Investigation, 4, 104–108. Lee, H. J., Lee, M. S., Kang, R. H., Kim, H., Kim, S. D., Kee, B. S., et al. (2005). Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depression and Anxiety, 21, 135–139. Liu, Y., Rimmler, J., Dennis, M. F., Ashley-Koch, A. E., Hauser, M. A., & Beckham, J. C. (2013). Association of variant rs4790904 in protein kinase C Alpha with posttraumatic stress disorder in a U.S. Caucasian and African–American Veteran Sample. Journal of Depression and Anxiety, 2, S4001. Logue, M. W., Baldwin, C., Guffanti, G., Melista, E., Wolf, E. J., Reardon, A. F., et al. (2013). A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Molecular Psychiatry, 18, 937–942. Logue, M. W., Solovieff, N., Leussis, M. P., Wolf, E. J., Melista, E., Baldwin, C., et al. (2013). The ankyrin-3 gene is associated with posttraumatic stress disorder and externalizing comorbidity. Psychoneuroendocrinology, 38, 2249–2257. Lu, A. T., Ogdie, M. N., Jarvelin, M. R., Moilanen, I. K., Loo, S. K., McCracken, J. T., et al. (2008). Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 147B, 1488–1494. Lyons, M. J., Genderson, M., Grant, M. D., Logue, M., Zink, T., McKenzie, R., et al. (2013). Gene–environment interaction of ApoE genotype and combat exposure on PTSD. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 162B, 762–769. Lyons, M. J., Goldberg, J., Eisen, S. A., True, W., Tsuang, M. T., Meyer, J. M., et al. (1993). Do genes influence exposure to trauma? A twin study of combat. American Journal of Medical Genetics, 48, 22–27. McGowan, P. O., & Szyf, M. (2010). Environmental epigenomics: understanding the effects of parental care on the epigenome. Essays in Biochemistry, 48, 275–287. Mehta, D., Klengel, T., Conneely, K. N., Smith, A. K., Altmann, A., Pace, T. W., et al. (2013). Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proceedings of the National Academy of Sciences of the United States of America, 110, 8302–8307. Mellman, T. A., Alim, T., Brown, D. D., Gorodetsky, E., Buzas, B., Lawson, W. B., et al. (2009). Serotonin polymorphisms and posttraumatic stress disorder in a trauma exposed African American population. Depression and Anxiety, 26, 993–997. Mineka, S., & Oehlberg, K. (2008). The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders. Acta Psychologica (Amsterdam), 127, 567–580. Morris, C. P., Baune, B. T., Domschke, K., Arolt, V., Swagell, C. D., Hughes, I. P., et al. (2012). KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence. Disease Markers, 33, 163–170. Mustapic, M., Pivac, N., Kozaric-Kovacic, D., Dezeljin, M., Cubells, J. F., & Muck-Seler, D. (2007). Dopamine beta-hydroxylase (DBH) activity and −1021C/T polymorphism of DBH gene in combat-related post-traumatic stress disorder. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 144B, 1087–1089. Myers, K. M., & Davis, M. (2002). Behavioral and neural analysis of extinction. Neuron, 36, 567–584. Navarro-Mateu, F., Escamez, T., Koenen, K. C., Alonso, J., & Sanchez-Meca, J. (2013). Meta-analyses of the 5-HTTLPR polymorphisms and post-traumatic stress disorder. PLoS One, 8, e66227. Nelson, E. C., Agrawal, A., Pergadia, M. L., Lynskey, M. T., Todorov, A. A., Wang, J. C., et al. (2009). Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults. Molecular Psychiatry, 14, 234–235. Nelson, E. C., Heath, A. C., Lynskey, M. T., Agrawal, A., Henders, A. K., Bowdler, L. M., et al. (2014). PTSD risk associated with a functional DRD2 polymorphism in heroin-dependent cases and controls is limited to amphetamine-dependent individuals. Addiction Biology, 9, 700–707. Norrholm, S. D., Jovanovic, T., Smith, A. K., Binder, E., Klengel, T., Conneely, K., et al. (2013). Differential genetic and epigenetic regulation of catechol-Omethyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder. Frontiers in Behavioral Neuroscience, 7, 30. Paolucci, E. O., Genuis, M. L., & Violato, C. (2001). A meta-analysis of the published research on the effects of child sexual abuse. Journal of Psychology, 135, 17–36. Perroud, N., Rutembesa, E., Paoloni-Giacobino, A., Mutabaruka, J., Mutesa, L., Stenz, L., et al. (2014). The Tutsi genocide and transgenerational transmission of
maternal stress: epigenetics and biology of the HPA axis. World Journal of Bioloigical Psychiatry, 15, 334–345. Pietrzak, R. H., Galea, S., Southwick, S. M., & Gelernter, J. (2013). Examining the relation between the serotonin transporter 5-HTTPLR genotype x trauma exposure interaction on a contemporary phenotypic model of posttraumatic stress symptomatology: a pilot study. Journal of Affective Disorders, 148, 123–128. Pivac, N., Kozaric-Kovacic, D., Grubisic-Ilic, M., Nedic, G., Rakos, I., Nikolac, M., et al. (2012). The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder. World Journal of Bioloigical Psychiatry, 13, 306–311. Ressler, K. J., Mercer, K. B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., et al. (2011). Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature, 470, 492–497. Rusiecki, J. A., Byrne, C., Galdzicki, Z., Srikantan, V., Chen, L., Poulin, M., et al. (2013). PTSD and DNA methylation in select immune function gene promoter regions: a repeated measures case-control study of U.S. Military Service Members. Frontiers in Psychiatry, 4, 56. Rusiecki, J. A., Chen, L., Srikantan, V., Zhang, L., Yan, L., Polin, M. L., et al. (2012). DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members. Epigenomics, 4, 29–40. Sapolsky, R. M. (2001). Atrophy of the hippocampus in posttraumatic stress disorder: how and when? Hippocampus, 11, 90–91. Sartor, C. E., Grant, J. D., Lynskey, M. T., McCutcheon, V. V., Waldron, M., Statham, D. J., et al. (2012). Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Archives of General Psychiatry, 69, 293–299. Sartor, C. E., McCutcheon, V. V., Pommer, N. E., Nelson, E. C., Grant, J. D., Duncan, A. E., et al. (2011). Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychological Medicine, 41, 1497–1505. Sayin, A., Kucukyildirim, S., Akar, T., Bakkaloglu, Z., Demircan, A., Kurtoglu, G., et al. (2010). A prospective study of serotonin transporter gene promoter (5-HTT gene linked polymorphic region) and intron 2 (variable number of tandem repeats) polymorphisms as predictors of trauma response to mild physical injury. DNA and Cell Biology, 29, 71–77. Schnurr, P. P. (2013). The changed face of PTSD diagnosis. Journal of Traumatic Stress, 26, 535–536. Schulz-Heik, R. J., Schaer, M., Eliez, S., Hallmayer, J. F., Lin, X., Kaloupek, D. G., et al. (2011). Catechol-O-methyltransferase Val158Met polymorphism moderates anterior cingulate volume in posttraumatic stress disorder. Bioloigical Psychiatry, 70, 1091–1096. Segman, R. H., Cooper-Kazaz, R., Macciardi, F., Goltser, T., Halfon, Y., Dobroborski, T., et al. (2002). Association between the dopamine transporter gene and posttraumatic stress disorder. Molecular Psychiatry, 7, 903–907. Shalev, A. Y., Ankri, Y., Israeli-Shalev, Y., Peleg, T., Adessky, R., & Freedman, S. (2012). Prevention of posttraumatic stress disorder by early treatment: results from the Jerusalem Trauma Outreach and Prevention study. Archives of General Psychiatry, 69, 166–176. Smith, A. K., Conneely, K. N., Kilaru, V., Mercer, K. B., Weiss, T. E., Bradley, B., et al. (2011). Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 156B, 700–708. Soliman, F., Glatt, C. E., Bath, K. G., Levita, L., Jones, R. M., Pattwell, S. S., et al. (2010). A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science, 327, 863–866. Solovieff, N., Roberts, A. L., Ratanatharathorn, A., Haloosim, M., De Vivo, I., King, A. P., et al. (2014). Genetic Association Analysis of 300 Genes Identifies a Risk Haplotype in SLC18A2 for Post-traumatic Stress Disorder in Two Independent Samples. Neuropsychopharmacology,. Epub 2014 Feb 14. Southam, E., & Garthwaite, J. (1993). The nitric oxide-cyclic GMP signalling pathway in rat brain. Neuropharmacology, 32, 1267–1277. Stevens, J. S., Almli, L. M., Fani, N., Gutman, D. A., Bradley, B., Norrholm, S. D., et al. (2014). PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 111, 3158–3163. Swagell, C. D., Lawford, B. R., Hughes, I. P., Voisey, J., Feeney, G. F., van Daal, A., et al. (2012). DRD2 C957T and TaqIA genotyping reveals gender effects and unique low-risk and high-risk genotypes in alcohol dependence. Alcohol and Alcoholism, 47, 397–403. Thakur, G. A., Joober, R., & Brunet, A. (2009). Development and persistence of posttraumatic stress disorder and the 5-HTTLPR polymorphism. Journal of Traumatic Stress, 22, 240–243. Toyokawa, S., Uddin, M., Koenen, K. C., & Galea, S. (2012). How does the social environment ‘get into the mind’? Epigenetics at the intersection of social and psychiatric epidemiology. Social Science & Medicine, 74, 67–74. True, W. R., Rice, J., Eisen, S. A., Heath, A. C., Goldberg, J., Lyons, M. J., et al. (1993). A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Archives of General Psychiatry, 50, 257–264. Uddin, M., Aiello, A. E., Wildman, D. E., Koenen, K. C., Pawelec, G., de Los Santos, R., et al. (2010). Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proceedings of the National Academy of Sciences of the United States of America, 107, 9470–9475. Uddin, M., Chang, S. C., Zhang, C., Ressler, K., Mercer, K. B., Galea, S., et al. (2013). Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment. Depression and Anxiety, 30, 251–258.
J. Voisey et al. / Journal of Anxiety Disorders 28 (2014) 873–883 Uddin, M., Galea, S., Chang, S. C., Aiello, A. E., Wildman, D. E., de los Santos, R., et al. (2011). Gene expression and methylation signatures of MAN2C1 are associated with PTSD. Disease Markers, 30, 111–121. Uddin, M., Galea, S., Chang, S. C., Koenen, K. C., Goldmann, E., Wildman, D. E., et al. (2013). Epigenetic signatures may explain the relationship between socioeconomic position and risk of mental illness: preliminary findings from an urban community-based sample. Biodemography and Social Biology, 59, 68–84. Valente, N. L., Vallada, H., Cordeiro, Q., Bressan, R. A., Andreoli, S. B., Mari, J. J., et al. (2011). Catechol-O-methyltransferase (COMT) val158met polymorphism as a risk factor for PTSD after urban violence. Journal of Molecular Neuroscience, 43, 516–523. Valente, N. L., Vallada, H., Cordeiro, Q., Miguita, K., Bressan, R. A., Andreoli, S. B., Mari, J. J., & Mello, M. F. (2011). Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF. Journal of Molecular Neuroscience, 44, 59–67. Voisey, J., Swagell, C. D., Hughes, I. P., Connor, J. P., Lawford, B. R., Young, R. M., & Morris, C. P. (2010). A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia. Behavioural Brain Functions, 6, 41. Voisey, J., Swagell, C. D., Hughes, I. P., Morris, C. P., van Daal, A., Noble, E. P., et al. (2009). The DRD2 gene 957C>T polymorphism is associated with posttraumatic stress disorder in war veterans. Depression and Anxiety, 26, 28–33. Wald, I., Degnan, K. A., Gorodetsky, E., Charney, D. S., Fox, N. A., Fruchter, E., et al. (2013). Attention to threats and combat-related posttraumatic stress symptoms: prospective associations and moderation by the serotonin transporter gene. Journal of the American Medical Association Psychiatry, 70, 401–408. Walsh, K., Uddin, M., Soliven, R., Wildman, D. E., & Bradley, B. (2014). Associations between the SS variant of 5-HTTLPR and PTSD among adults with histories of childhood emotional abuse: results from two African American independent samples. Journal of Affective Disorders, 161, 91–96. Wang, L., Cao, C., Wang, R., Qing, Y., Zhang, J., & Zhang, X. Y. (2013). PAC1 receptor (ADCYAP1R1) genotype is associated with PTSD’s emotional numbing symptoms in Chinese earthquake survivors. Journal of Affective Disorders, 150, 156–159. Wang, Z., Baker, D. G., Harrer, J., Hamner, M., Price, M., & Amstadter, A. (2011). The relationship between combat-related posttraumatic stress disorder and the 5-HTTLPR/rs25531 polymorphism. Depression and Anxiety, 28, 1067–1073. White, S., Acierno, R., Ruggiero, K. J., Koenen, K. C., Kilpatrick, D. G., Galea, S., et al. (2013). Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults. Journal of Anxiety Disorders, 27, 678–683. Wilker, S., Kolassa, S., Vogler, C., Lingenfelder, B., Elbert, T., Papassotiropoulos, A., et al. (2013). The role of memory-related gene WWC1 (KIBRA) in lifetime
883
posttraumatic stress disorder: evidence from two independent samples from African conflict regions. Bioloigical Psychiatry, 74, 664–671. Wolf, E. J., Rasmusson, A. M., Mitchell, K. S., Logue, M. W., Baldwin, C. T., & Miller, M. W. (2014). A genome-wide association study of clinical symptoms of dissociation in a trauma-exposed sample. Depression and Anxiety, 31, 352–360. Wolfsohn, J. M. (1918). The predisposing factors of war psycho-neuroses. Lancet, 191, 177–181. Xie, P., Kranzler, H. R., Farrer, L., & Gelernter, J. (2012). Serotonin transporter 5HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 159B, 644–652. Xie, P., Kranzler, H. R., Poling, J., Stein, M. B., Anton, R. F., Brady, K., et al. (2009). Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Archives of General Psychiatry, 66, 1201–1209. Xie, P., Kranzler, H. R., Poling, J., Stein, M. B., Anton, R. F., Farrer, L. A., et al. (2010). Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology, 35, 1684–1692. Xie, P., Kranzler, H. R., Yang, C., Zhao, H., Farrer, L. A., & Gelernter, J. (2013). Genomewide association study identifies new susceptibility loci for posttraumatic stress disorder. Bioloigical Psychiatry, 74, 656–663. Yehuda, R. (2001). Biology of posttraumatic stress disorder. The Journal of Clinical Psychiatry, 62(Suppl 17), 41–46. Yehuda, R., Daskalakis, N. P., Desarnaud, F., Makotkine, I., Lehrner, A. L., Koch, E., et al. (2013). Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Frontiers in Psychiatry, 4, 118. Yehuda, R., Daskalakis, N. P., Lehrner, A., Desarnaud, F., Bader, H. N., Makotkine, I., et al. (2014). Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in holocaust survivor offspring. The American Journal of Psychiatry, 171, 872–880. Yehuda, R., Flory, J. D., Bierer, L. M., Henn-Haase, C., Lehrner, A., Desarnaud, F., et al. (2014). Lower methylation of glucocorticoid receptor gene promoter 1 in peripheral blood of veterans with posttraumatic stress disorder. Bioloigical Psychiatry, Epub ahead of print. Young, R. M., Lawford, B. R., Noble, E. P., Kann, B., Wilkie, A., Ritchie, T., et al. (2002). Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol and Alcoholism, 37, 451–456. Zhang, H., Ozbay, F., Lappalainen, J., Kranzler, H. R., van Dyck, C. H., Charney, D. S., et al. (2006). Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer’s disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. American Journal of Medical Genetics, B: Neuropsychiatric Genetics, 141B, 387–393.