The Role of Memory-related Gene WWC1 (KIBRA) in Lifetime Posttraumatic Stress Disorder: Evidence from Two Independent Samples from African Conflict Regions

doi:10.1016/j.biopsych.2013.02.022

Biological Psychiatry

Volume 74, Issue 9, 1 November 2013, Pages 664-671

https://doi.org/10.1016/j.biopsych.2013.02.022 Get rights and content

Background

Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common WWC1 alleles influence the risk for a lifetime diagnosis of PTSD.

Methods

Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n = 392, Rwanda, and n = 399, Northern Uganda, respectively). Array-based single nucleotide polymorphism (SNP) genotyping was performed. The influence of WWC1 tagging SNPs and traumatic load on lifetime PTSD was estimated by means of logistic regression models with correction for multiple comparisons in the Rwandan sample. Replication analysis was performed in the independent Ugandan sample.

Results

An association of two neighboring SNPs in almost complete linkage disequilibrium, rs10038727 and rs4576167, with lifetime PTSD was discovered in the Rwandan sample. Although each traumatic event added to the probability of lifetime PTSD in a dose-dependent manner in both genotype groups, carriers of the minor allele of both SNPs displayed a diminished risk (p = .007, odds ratio = .29 [95% confidence interval = .15–.54]). This effect was confirmed in the independent Ugandan sample.

Conclusions

This study reveals an association between two WWC1 SNPs and the likelihood of PTSD development, indicating that this memory-related gene might be involved in processes that occur in response to traumatic stress and influence the strengthening of fear memories.

Section snippets

Rwandan Sample

A total number of 466 survivors of the Rwandan genocide were interviewed in the refugee settlement Nakivale, Uganda, in 2006–2007 47, 48, 49, 50. However, after accounting for missing data (exclusion of n = 20) and genotyping errors (exclusion of n = 54), analyses were based on a sample of n = 392 (194 women, mean age = 34.62, SD = 5.89). All procedures were approved by the Ethics Committee of the University of Konstanz, Germany, and the University of Mbarara, Uganda.

Ugandan Sample

A sample of 454 survivors

Rwandan Sample

Two neighboring SNPs within WWC1, rs10038727 and rs4576167, were significantly associated with a diminished risk of lifetime PTSD development (Figure 1, upper panel) with and without inclusion of the covariate’s age, sex, or comorbid depressive symptoms (HSCL-D). A main-effect model of traumatic load and genotype with HSCL-D as a covariate was chosen on the basis of goodness-of-fit parameters. The two SNPs were in almost complete LD (r² = .99; Figure 1, lower panel) and showed similar genotype

Discussion

We found a strong association of two SNPs within WWC1, rs10038727 and rs4576167, with a reduced risk to lifetime PTSD development in two independent samples. This novel association points toward a potential clinical relevance of this gene in disorders that involve the formation of pathological fear memories.

We replicated the typical dose-dependent effect of traumatic load on the risk of lifetime PTSD in both genotype groups. However, minor allele carriers of the two SNPs identified exhibited

References (74)

A. Ehlers et al.
A cognitive model of posttraumatic stress disorder
Behav Res Ther
(2000)
B. Rockstroh et al.
Traces of fear in the neural web: Magnetoencephalographic responding to arousing pictorial stimuli
Int J Psychophysiol
(2010)
T. Elbert et al.
Trauma-related impairment in children: A survey in Sri Lankan provinces affected by armed conflict
Child Abuse Negl
(2009)
F.L. Woon et al.
Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: A meta-analysis
Prog Neuropsychopharmacol Biol Psychiatry
(2010)
A. Karl et al.
A meta-analysis of structural brain abnormalities in PTSD
Neurosci Biobehav Rev
(2006)
J. Kremerskothen et al.
Characterization of KIBRA, a novel WW domain-containing protein
Biochem Biophys Res Commun
(2003)
T.C. Bates et al.
Association of KIBRA and memory
Neurosci Lett
(2009)
C. Preuschhof et al.
KIBRA and CLSTN2 polymorphisms exert interactive effects on human episodic memory
Neuropsychologia
(2010)
K. Schaper et al.
KIBRA gene variants are associated with episodic memory in healthy elderly
Neurobiol Aging
(2008)
E. Vassos et al.
Evidence of association of KIBRA genotype with episodic memory in families of psychotic patients and controls
J Psychiatr Res
(2010)

B. Nacmias et al.

KIBRA gene variants are associated with episodic memory performance in subjective memory complaints

Neurosci Lett

(2008)

S. Johannsen et al.

Temporal-spatial expression and novel biochemical properties of the memory-related protein KIBRA

Neuroscience

(2008)

K. Büther et al.

KIBRA is a novel substrate for protein kinase Czeta

Biochem Biophys Res Commun

(2004)

L. Makuch et al.

Regulation of AMPA receptor function by the human memory-associated gene KIBRA

Neuron

(2011)

I.-T. Kolassa et al.

The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism

Biol Psychiatry

(2010)

M.R. Milad et al.

Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder

Biol Psychiatry

(2009)

Z. Steel et al.

Association of torture and other potentially traumatic events with mental health outcomes among populations exposed to mass conflict and displacement: A systematic review and meta-analysis

JAMA

(2009)

M. Jakupcak et al.

Posttraumatic stress disorder as a risk factor for suicidal ideation in Iraq and Afghanistan War veterans

J Trauma Stress

(2009)

H. Glaesmer et al.

The association of traumatic experiences and posttraumatic stress disorder with physical morbidity in old age: A German population-based study

Psychosom Med

(2011)

I.-T. Kolassa et al.

Spontaneous remission from PTSD depends on the number of traumatic event types experienced

Psychol Trauma

(2010)

F. Neuner et al.

Psychological trauma and evidence for enhanced vulnerability for posttraumatic stress disorder through previous trauma among West Nile refugees

BMC Psychiatry

(2004)

M.B. Stein et al.

Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: A twin study

Am J Psychiatry

(2002)

W.R. True et al.

A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms

Arch Gen Psychiatry

(1993)

T. Elbert et al.

Burnt into memory

Nature

(2002)

C.R. Brewin et al.

A dual representation theory of posttraumatic stress disorder

Psychol Rev

(1996)

C.R. Brewin et al.

Intrusive images in psychological disorders: Characteristics, neural mechanisms, and treatment implications

Psychol Rev

(2010)

I.-T. Kolassa et al.

Structural and functional neuroplasticity in relation to traumatic stress

Curr Dir Psychol Sci

(2007)

S. Wilker et al.

The formation of a neural fear network in posttraumatic stress disorder: Insights from molecular genetics [published online ahead of print March 18]

Clin Psychol Sci

(2013)

S.U. Qureshi et al.

Does PTSD impair cognition beyond the effect of trauma?

J Neuropsychiatry Clin Neurosci

(2011)

C.R. Brewin et al.

Memory for emotionally neutral information in posttraumatic stress disorder: A meta-analytic investigation

J Abnorm Psychol

(2007)

R.M. Sapolsky

Chickens, eggs and hippocampal atrophy

Nat Neurosci

(2002)

M.W. Gilbertson et al.

Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

Nat Neurosci

(2002)

M.W. Gilbertson et al.

Neurocognitive function in monozygotic twins discordant for combat exposure: Relationship to posttraumatic stress disorder

J Abnorm Psychol

(2006)

A. Papassotiropoulos et al.

Common Kibra alleles are associated with human memory performance

Science

(2006)

O.P. Almeida et al.

KIBRA genetic polymorphism influences episodic memory in later life, but does not increase the risk of mild cognitive impairment

J Cell Mol Med

(2008)

N. Hayashi et al.

KIBRA genetic polymorphism influences episodic memory in Alzheimer’s disease, but does not show association with disease in a Japanese cohort

Dement Geriatr Cogn Disord

(2010)

Y. Yasuda et al.

Association study of KIBRA gene with memory performance in a Japanese population

World J Biol Psychiatry

(2010)

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Before conclusions can be drawn however these genes must be replicated in larger GWASs and meta-analyses currently planned by the PGC PTSD working group (Koenen et al., 2013). We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, either showing a main effect for the genetic marker, and/or a significant GxE interaction (Amstadter et al., 2009, 2011; Binder et al., 2008; Boscarino et al., 2011; Cao et al., 2013; Comings et al., 1996; Dragan and Oniszczenko, 2009; Gillespie et al., 2013; Goenjian et al., 2012; Grabe et al., 2009; Guffanti et al., 2013; Hauer et al., 2011; Kolassa et al., 2010; Logue et al., 2013a,b; Lyons et al., 2013; Mellman et al., 2009; Nelson et al., 2009; Ressler et al., 2011; Segman et al., 2002; Solovieff et al., 2014; Voisey et al., 2010; Wilker et al., 2013; Xie et al., 2013). Since most studies were performed in subjects of either European or African descent, we used these specific ancestry groups for comparison with MRS. We found that most of the 25 candidate genes showed nominally significant associations in MRS for at least one of the SNPs tested.
Research on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.
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The array produced >800 K directly genotyped and >21 M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR = 1.47, SE = 0.06, p = 2.04 × 10⁻⁹), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n = 25 genes, p < 5 × 10⁻⁶) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ.
This first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders.
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The same authors reported large deficits in hippocampal long term potentiation as well as in fear memory performance in adult KIBRA knock-out mice (Makuch et al., 2011). Due to this convergent line of evidence suggesting a pivotal role of KIBRA in human memory, Wilker et al. (2013) investigated whether common WWC1 alleles also predicted the risk to develop strong traumatic memories in survivors of mass conflict. Employing high-throughput technology, the authors simultaneously investigated 115 tagged WWC1 SNPs in two independent samples of survivors of the Rwandan genocide, and the conflict with the rebel group Lord’s Resistance Army in Northern Uganda, respectively.
A good memory for emotionally arousing experiences may be intrinsically adaptive, as it helps the organisms to predict safety and danger and to choose appropriate responses to prevent potential harm. However, under conditions of repeated exposure to traumatic stressors, strong emotional memories of these experiences can lead to the development of trauma-related disorders such as posttraumatic stress disorder (PTSD). This syndrome is characterized by distressing intrusive memories that can be so intense that the survivor is unable to discriminate past from present experiences.
This selective review on the role of memory-related genes in PTSD etiology is divided in three sections. First, we summarize studies indicating that the likelihood to develop PTSD depends on the cumulative exposure to traumatic stressors and on individual predisposing risk factors, including a substantial genetic contribution to PTSD risk. Second, we focus on memory processes supposed to be involved in PTSD etiology and present evidence for PTSD-associated alterations in both implicit (fear conditioning, fear extinction) and explicit memory for emotional material. This is supplemented by a brief description of structural and functional alterations in memory-relevant brain regions in PTSD. Finally, we summarize a selection of studies indicating that genetic variations found to be associated with enhanced fear conditioning, reduced fear extinction or better episodic memory in human experimental studies can have clinical implications in the case of trauma exposure and influence the risk of PTSD development. Here, we focus on genes involved in noradrenergic (ADRA2B), serotonergic (SLC6A4), and dopaminergic signaling (COMT) as well as in the molecular cascades of memory formation (PRKCA and WWC1). This is supplemented by initial evidence that such memory-related genes might also influence the response rates of exposure-based psychotherapy or pharmacological treatment of PTSD, which underscores the relevance of basic memory research for disorders of altered memory functioning such as PTSD.

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Archival ReportThe Role of Memory-related Gene WWC1 (KIBRA) in Lifetime Posttraumatic Stress Disorder: Evidence from Two Independent Samples from African Conflict Regions

Background

Methods

Results

Conclusions

Section snippets

Rwandan Sample

Ugandan Sample

Rwandan Sample

Discussion

Behav Res Ther

Int J Psychophysiol

Child Abuse Negl

Prog Neuropsychopharmacol Biol Psychiatry

Neurosci Biobehav Rev

Biochem Biophys Res Commun

Neurosci Lett

Neuropsychologia

Neurobiol Aging

J Psychiatr Res

Neurosci Lett

Neuroscience

Biochem Biophys Res Commun

Neuron

Biol Psychiatry

Biol Psychiatry

Association of torture and other potentially traumatic events with mental health outcomes among populations exposed to mass conflict and displacement: A systematic review and meta-analysis

JAMA

Posttraumatic stress disorder as a risk factor for suicidal ideation in Iraq and Afghanistan War veterans

J Trauma Stress

The association of traumatic experiences and posttraumatic stress disorder with physical morbidity in old age: A German population-based study

Psychosom Med

Spontaneous remission from PTSD depends on the number of traumatic event types experienced

Psychol Trauma

Psychological trauma and evidence for enhanced vulnerability for posttraumatic stress disorder through previous trauma among West Nile refugees

BMC Psychiatry

Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: A twin study

Am J Psychiatry

A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms

Arch Gen Psychiatry

Burnt into memory

Nature

A dual representation theory of posttraumatic stress disorder

Psychol Rev

Intrusive images in psychological disorders: Characteristics, neural mechanisms, and treatment implications

Psychol Rev

Structural and functional neuroplasticity in relation to traumatic stress

Curr Dir Psychol Sci

The formation of a neural fear network in posttraumatic stress disorder: Insights from molecular genetics [published online ahead of print March 18]

Clin Psychol Sci

Does PTSD impair cognition beyond the effect of trauma?

J Neuropsychiatry Clin Neurosci

Memory for emotionally neutral information in posttraumatic stress disorder: A meta-analytic investigation

J Abnorm Psychol

Chickens, eggs and hippocampal atrophy

Nat Neurosci

Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

Nat Neurosci

Neurocognitive function in monozygotic twins discordant for combat exposure: Relationship to posttraumatic stress disorder

J Abnorm Psychol

Common Kibra alleles are associated with human memory performance

Science

KIBRA genetic polymorphism influences episodic memory in later life, but does not increase the risk of mild cognitive impairment

J Cell Mol Med

KIBRA genetic polymorphism influences episodic memory in Alzheimer’s disease, but does not show association with disease in a Japanese cohort

Dement Geriatr Cogn Disord

Association study of KIBRA gene with memory performance in a Japanese population

World J Biol Psychiatry

Archival Report
The Role of Memory-related Gene WWC1 (KIBRA) in Lifetime Posttraumatic Stress Disorder: Evidence from Two Independent Samples from African Conflict Regions