rs9470080

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.

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).

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.