Association of FKBP5, COMT and CHRNA5 polymorphisms with PTSD among outpatients at risk for PTSD.
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ABSTRACT:
SUBMITTER: Boscarino JA
PROVIDER: S-EPMC3415886 | biostudies-literature | 2011 Jun
REPOSITORIES: biostudies-literature
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Association of FKBP5, COMT and CHRNA5 polymorphisms with PTSD among outpatients at risk for PTSD.
Boscarino Joseph A JA Erlich Porat M PM Hoffman Stuart N SN Rukstalis Margaret M Stewart Walter F WF
Psychiatry research 20110406 1
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Project description:OBJECTIVE:The study aim was to assess the cumulative burden of polymorphisms located within four genetic loci previously associated with posttraumatic stress disorder (PTSD) among outpatients at risk for PTSD. METHODS:Diagnostic interviews were completed and DNA samples collected among 412 pain patients to determine if FKBP5 (rs9470080), COMT (rs4680), CHRNA5 (rs16969968), and CRHR1 (rs110402) single nucleotide polymorphisms were cumulatively associated with increased risk for PTSD. RESULTS:In bivariate analyses, it was found that a count of specific PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (allele range = 0-6, mean count = 2.92, standard deviation = 1.36) was associated with lifetime (t [409] = 3.430, P = 0.001) and early onset PTSD (t [409] = 4.239, P = 0.000028). In logistic regression, controlling for demographic factors, personality traits, and trauma exposures, this risk allele count remained associated with both lifetime (odds ratio = 1.49, P = 0.00158) and early onset PTSD (odds ratio = 2.36, P = 0.000093). Interaction effects were also detected, whereby individuals with higher risk allele counts and higher trauma exposures had an increased risk of lifetime PTSD (allele count × high trauma, P = 0.026) and early onset PTSD (allele count × high trauma, P = 0.016) in these logistic regressions. Those with no or few risk alleles appeared resilient to PTSD, regardless of exposure history. CONCLUSION:A cumulative risk allele count involving four single nucleotide polymorphisms located within the FKBP5, COMT, CHRNA5, and CRHR1 genes are associated with PTSD. Level of trauma exposure interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment.
| S-EPMC3333786 | biostudies-literature
Project description:ContextIn addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability.ObjectiveTo increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene x environment interactions of child abuse, level of non-child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5.Design, setting, and participantsA cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non-child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007.Main outcome measuresSeverity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non-child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus.ResultsLevel of child abuse and non-child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs > or =2 types of abuse, 20.93 [14.32]; and for no non-child abuse trauma, 3.58 [6.27] vs > or =4 types, 16.74 [12.90]; P < .001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non-child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P = .0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene x environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non-child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test.ConclusionsFour SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.
| S-EPMC2441757 | biostudies-literature
Project description:BackgroundMemory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume.MethodsRecent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume.ResultsWe included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume.LimitationsThe direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both.ConclusionOur findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.
| S-EPMC5373706 | biostudies-literature
Project description:ObjectivesCommon genetic SNPs in two genes, encoding catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR), which are interconnected with COMT gene regulation, have been reported to contribute to schizophrenia risk. In this study, we evaluated the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk with a case-control study in a Korean population.MethodsWe performed a case-control study by genotyping analysis using 360 cases and 348 controls in Korean subjects to determine the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk.ResultsFour functional SNPs in COMT (Val158Met and rs165599) and MTHFR (C677T and A1298C) were genotyped by primer extension assay. None of the genotype distributions for the four SNPs was significantly different between cases and controls. Stratified analysis did not show any significant gender difference for any polymorphism. In addition, we found no evidence of a gene-gene interaction in the analysis of combined genotypes.ConclusionOur results suggest no significant association between the selected functional polymorphisms of COMT or MTHFR in Korean schizophrenia subjects. However, further studies are required to confirm our findings in a larger number of subjects.
| S-EPMC3013321 | biostudies-literature
Project description:Lung cancer is the most frequent cancer among men in many countries. It is the result of interactions between genetic and environmental factors, among which tobacco smoking is a key environmental factor. CHRNA5, Cholinergic Receptor, Neuronal Nicotinic, Alpha Polypeptide-5, was previously reported to be associated with lung cancer risk. To identify the genetic susceptibility and tobacco smoking that influence lung cancer risk in Han population, we performed a case-control study in 228 patients and 301 controls. These data were compared using the χ(2)-test, genetic model analysis, and haplotype analysis. rs495956, rs680244, rs601079, rs555018, 588765 and rs11637635 showed an increased risk of lung cancer in both allelic model and genetic mode analysis. The genotype G/A-A/A of rs11637635 was most strongly associated with a 2.17-fold increased risk of lung cancer in dominant model (p = 0.018). One SNP, rs684513, was associated with a 0.645-fold decreased risk (p = 0.033) in allelic model analysis. By haplotype association analysis, haplotype sequences CTTATCAAAGA and GA of CHRNA5 were found to be associated with a 2.03-fold and 1.91-fold increased lung cancer risk (p < 0.05). Our results, combined with those from previous studies, suggest that genetic variation in CHRNA5 may influence susceptibility to lung cancer among Han smokers.
| S-EPMC4656745 | biostudies-literature
Project description:Tobacco smoking has been found to increase after the experience of a traumatic event and has been associated with posttraumatic stress disorder (PTSD). Initiation and persistence of cigarette smoking is moderately heritable; two recent investigations have implicated the COMT Val158Met (also known as rs4680) polymorphism in smoking age of initiation, dependence, as well as in quantity and frequency of smoking. To examine a possible association of COMT Val158Met and posttrauma increases in cigarette smoking, we studied 614 adults from the 2004 Florida Hurricane Study who returned saliva DNA samples via mail. PTSD was strongly associated with increased smoking. Moreover, each COMT Val158Met 'Met' allele predicted a 2.10-fold risk of smoking post-hurricane, independent of PTSD; follow-up analyses revealed that this finding was primarily driven by European-American males. This study represents the first genetic association study (to our knowledge) of smoking behavior following an acute stressor.
| S-EPMC2808117 | biostudies-literature
Project description:BackgroundThe role of gene-environment interactions in the pathogenesis of depression is unclear. Previous studies addressed vulnerability for depression after childhood adversity and stressful life events among carriers of numerous specific genetic variants; however, the importance of individual genetic variants, the environmental exposures with which they interact, and the magnitude of the risk conveyed by these interactions remain elusive.MethodsWe included 7,320 people with a first primary cancer identified in the prospective Diet, Cancer and Health study in an exposed-only cohort study. The mean age of the individuals was 68 years (5th, 95th percentiles: 58, 78) at cancer diagnosis. Using Cox regression models and cumulative incidence plots, we analyzed the associations between genetic variants in 5-HTTLPR, BDNF, HTR1A, COMT, and FKBP5 and use of antidepressants as well as hospital contact for depression after diagnosis of cancer.ResultsOverall, we observed no statistically significant associations, with nonsignificant hazard ratio estimates for use of antidepressants of 0.95-1.07.ConclusionsThis study of elderly people indicates that it is unlikely that the investigated genetic variants are clinically relevantly associated with depression after diagnosis of cancer. The mechanisms for gene-environment interactions in younger individuals are probably different, and we advise caution in extrapolating our results to early life stress. However, conclusion from the present study might be generalizable to elderly persons exposed to other stressful life events.
| S-EPMC5933050 | biostudies-literature
Project description:AIM:To explore the potential association between single-nucleotide polymorphisms (SNPs) and haplotypes of the CHRNA5-CHRNA3-CHRNB4 gene cluster and the non-small cell lung cancer (NSCLC) susceptibility in never-smoking Chinese. METHODS:A case-control study was conducted with 200 NSCLC patients and 200 healthy controls, matched on age and sex. Five SNPs distributed in CHRNA5-CHRNA3-CHRNB4 gene cluster were selected for genotyping. The association between genotype and lung cancer risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses with adjustment for gender and age. RESULTS:For CHRNA3 rs578776 status, data were available in 199 NSCLC patients and 199 controls. The G/G homozygote in CHRNB4 rs7178270 had a reduced risk of developing NSCLC (OR = 0.553; 95% CI = 0.309-0.989; P = .0437), especially squamous cell carcinoma (SQC) (OR = 0.344; 95% CI = 0.161-0.732; P = .0043), compared with those who carry at least one C allele (C/C and C/G). The polymorphisms of rs578776, rs938682, rs17486278, and rs11637635 were not significantly different between controls and cases or between controls and histologic subgroups, adenocarcinoma and SQC, respectively. CONCLUSIONS:In our study, we found that the SNP of CHRNB4 rs7178270 is significantly associated with reduced risk of NSCLC, especially with reduced risk of SQC in never-smoking Chinese population.
| S-EPMC3567724 | biostudies-literature
Project description:The FKBP5 polymorphism is a key regulator of the glucocorticoid system underpinning stress responsivity, and risk alleles can increase vulnerability for developing posttraumatic stress disorder. To delineate the specific role of FKBP5 risk alleles unencumbered by the confounds of psychopathology, this study investigated whether high-risk alleles of the FKBP5 polymorphism are characterized by distinctive neural activity during resting state. Thirty-seven healthy participants were selected on the basis of four SNPs in the FKBP5 gene region (rs3800373, rs9296158, rs1360780 and rs9470080) to determine participants who were carriers of the FKBP5 high- and low-risk alleles. Spatial maps, power spectra and connectivity in neural networks active during resting state were assessed with functional magnetic resonance imaging (fMRI). During resting-state fMRI, FKBP5 low-risk allele group displayed more power in the low frequency range (<0.1 Hz) than the high-risk allele group, who had significantly more power in higher frequency bins (>0.15 Hz). This difference was apparent only in a frontotemporoparietal network underpinning salience detection and emotion processing. This study provides initial evidence that the risk alleles of the FKBP5 polymorphism are associated with different resting-state activity in a frontotemporal-parietal network, and may point to mechanisms underpinning high-risk carriers' vulnerability to severe stress reactions.
| S-EPMC5315540 | biostudies-literature
Project description:BackgroundSchizophrenia is a complex mental disease whose cause is still unknown. Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in various neurological disorders, including schizophrenia. The previous reports have shown that CHRNA polymorphisms were involved in schizophrenia. This study is to explore the potential association between CHRNA5 (OMIM#118505) polymorphisms and schizophrenia susceptibility in a Chinese population.Methods and resultsA case-control study was conducted with 384 schizophrenia patients and 687 controls. We genotyped eight single nucleotide polymorphisms (SNPs) distributed in CHRNA5. Regulome DB, HaploReg, and GTEx databases were used to calculate possible functional effects of the polymorphisms. The χ2 test, genetic model analysis, and haplotype analysis were involved in assessing genetic association between variants and schizophrenia risk. The results exhibited that rs17486278 (NC_000015.10:g.78575140A>C) was associated with a decreased risk of schizophrenia on the basis of the recessive model (adjusted OR = 0.37, 95%CI: 0.15-0.93) in females. Moreover, we found that the four variants rs588765, rs6495306, rs680244, rs692780 were extremely significant after being stratified by ≥45 years.ConclusionsOverall, our findings supported that the potential association existed between CHRNA5 polymorphisms and schizophrenia susceptibility in a Chinese population. But, large sample validation is needed to enhance the accuracy of our results.
| S-EPMC6732284 | biostudies-literature