rs9296158

Gene-based meta-analysis of 24 studies examining hypothalamic-pituitary-adrenal (HPA) axis genes and posttraumatic stress disorder (PTSD) risk. SNP-level meta-analyses identified two variants nominally associated with PTSD after multiple testing correction: rs9296158 in FKBP5 (p = 0.001) and rs258747 in NR3C1 (p = 0.001). Gene-level meta-analyses showed significant associations with PTSD for NR3C1 (p = 0.003), CRHR1 (p = 0.017), and FKBP5 (p = 0.011), with NR3C1 and FKBP5 showing robust signals in sensitivity analyses.

This international doctoral thesis examined gene-physical activity interactions in fibromyalgia through six studies analyzing 64 SNPs across 34 candidate genes in Spanish women. The case-control study (314 fibromyalgia cases vs. 112 controls) identified associations of rs841 (GCH1), rs1799971 (OPRM1), and rs2097903 (COMT) with fibromyalgia susceptibility (p=0.04, p=0.02, and p=0.04 respectively). Cross-sectional studies (n=274-276 fibromyalgia patients) found that SCN9A rs4453709 and other genetic polymorphisms interacted with physical activity to influence pain, fatigue, and resilience outcomes.

A candidate gene association study of 368 healthy adults examined genetic variation in FKBP5 and CRHR1 in relation to cortisol response to acute psychosocial stress (Trier Social Stress Test). rs4713902 in FKBP5 showed the strongest association with baseline cortisol (p=0.0004, dominant model). Three CRHR1 SNPs (rs7209436, rs110402, rs242924) were associated with peak cortisol response (p=0.0029-0.0047, recessive models). Sex-specific effects and interactions with trait anxiety were observed.

Cross-sectional study of 411 Italian male prisoners examining gene-environment interactions between FKBP5 haplotypes (rs3800373, rs9296158, rs1360780, rs9470080) and childhood trauma in predicting aggressive behavior. FKBP5 H2/H2 diplotype showed significant association with lifetime aggression (BGHA, P=.012) and violent behavior in jail (P=.025) only in individuals exposed to childhood trauma, particularly physical abuse. No main effect of FKBP5 was observed; the interaction was significant (P=.004; P=.01 after FDR correction). H1 haplotype carriers had increased risk of substance dependence (OR 1.8, 95% CI 1.16-2.70).

Study of 211 participants (primarily African American, low-income) investigated interactions of FKBP5 SNP rs9296158 with PTSD symptoms on glucocorticoid receptor sensitivity and gene expression. Risk allele A carriers showed increased GR sensitivity (cortisol suppression P=.03) and altered gene expression patterns in PTSD. FKBP5 SNP×PTSD symptom interaction significantly predicted expression of 41 transcripts (including FKBP5 and IL18R1), with replication in 98 independent samples, suggesting FKBP5 polymorphisms define distinct PTSD endocrine subtypes.

This review examines gene-environment interactions in stress-related psychiatric disorders, focusing on CRHR1 and FKBP5 genes. Authors report that CRHR1 polymorphisms (rs7209436, rs110402, rs242924) interact with childhood abuse to predict adult depression, while FKBP5 variants (rs3800373, rs9296158) interact with child abuse to predict adult PTSD symptoms. The paper integrates human genetic association findings with preclinical research on amygdala-HPA axis development, proposing a model where gene-environment interactions during developmental critical periods mediate stress resilience and psychiatric vulnerability.

This study examined gene-environment (G×E) interactions between HPA axis variants (CRHR1, NR3C1, FKBP5) and childhood trauma on anxiety sensitivity in South African adolescents (n=951). Significant associations and interactions were found in gender- and ethnicity-specific analyses, including FKBP5 rs9296158 (p=0.025) and rs737054 (p=0.045) in Coloured males, and protective effects of NR3C1 rs190488 (p=0.009) and rs10482605 (p=0.036) with increasing trauma in Xhosa participants.

This cross-sectional study of 762 African American adults found that four FKBP5 SNPs (rs9296158, rs3800373, rs1360780, rs9470080; minimum P=0.0004) significantly interacted with severity of childhood abuse to predict adult PTSD symptoms, independent of non-child abuse trauma exposure, depression severity, age, sex, and genetic ancestry. The SNPs showed no main effects on PTSD or interactions with non-child abuse trauma, suggesting a specific gene-by-childhood-environment interaction mechanism.

This doctoral thesis conducted multiple candidate gene association studies in 274-426 southern Spanish women with fibromyalgia to investigate gene-physical activity/sedentary behavior interactions with pain, fatigue, and resilience. Study III identified rs841 (GCH1) GG genotype (OR=0.61, p=0.04) and rs2097903 (COMT) AT/TT genotypes (OR=1.66, p=0.04) associated with fibromyalgia susceptibility, and confirmed rs1799971 (OPRM1) GG genotype (OR=0.58, p=0.02) confers genetic risk. Study IV found rs6311/rs6313 (HTR2A) polymorphisms individually associated with algometer pain score, and gene-sedentary behavior interactions involving rs4680/rs165599 (COMT), rs1383914 (ADRA1A), rs12994338/rs4453709 (SCN9A), and rs6860 (CHMP1A) significantly associated with pain outcomes. SCN9A emerged as most robust gene for fibromyalgia phenotype.