rs25531

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.

This review examines neurogenetic and neuropharmacological correlates of opioid use disorder (OUD) with emphasis on ancestry-specific genetic risk profiles. The paper identifies multiple genes involved in the reward pathway (DRD2, DRD3, DRD4, OPRM1, OPRK1, OPRD1, BDNF, NRXN3, COMT, SLC6A4, KCNC1, KCNG2) and their variants associated with OUD susceptibility and treatment response across different ethnic populations, highlighting critical research disparities where African Americans and Hispanics have been underrepresented in genetic association studies.

This PhD thesis presents four genetic and epigenetic studies investigating risk factors for suicidal behavior in schizophrenia. Study 1 (n=241 schizophrenia patients) found that only rs2661319 in RGS4 was significantly associated with suicide attempt (p=0.002) among 384 SNPs tested, with RGS4 showing lower potential methylation in attempters (55% vs 65%, p=0.005). Studies 2-4 examined HTR2A and HTR1B methylation and expression in smaller samples (n=47-80) but found no strong evidence that genetic or epigenetic factors significantly predict suicidal behavior. Overall conclusion: no robust genetic or epigenetic predictors of suicide were identified in this schizophrenia population.

This review examines the genetic and epigenetic basis of Tourette Syndrome (TS), a neurodevelopmental disorder with high heritability (0.45-0.77). The paper reviews candidate gene associations including variants in SLITRK1 (rs9593835, rs9546538, rs9531520), DRD2/ANKK1 (rs1800497), ADORA1/ADORA2A (rs2228079, rs5751876), and other dopaminergic genes, along with a large GWAS in 1285 cases and 4964 controls highlighting rs7868992 in COL27A1. The review proposes that epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) may link genetic susceptibility with environmental factors in TS pathogenesis.

A genome-wide association study of 484 trauma-exposed individuals identified ten SNPs with suggestive associations (p < 10^-5) with dissociative symptoms (derealization and depersonalization) in PTSD. The strongest association was rs263232 (β = 1.4, p = 6.12 × 10^-7) in ADCY8, and rs71534169 (β = 1.63, p = 3.79 × 10^-6) in DPP6. No SNPs met genome-wide significance. These genes are implicated in synaptic plasticity, memory consolidation, and neuronal excitability, suggesting biological pathways underlying dissociative phenomena.

This gene-environment interaction study examined 4,504 Caucasian subjects from two independent cohorts (SHIP-LEGEND and SHIP-TREND-0) to assess how variants in serotonergic pathway genes TPH2 (rs7305115) and 5-HTTLPR moderate depression risk after childhood abuse. The three-way interaction between abuse, TPH2 GG genotype, and 5-HTTLPR SS genotype showed significant association with depression severity (p=0.023), with GG/SS carriers exposed to abuse displaying mean BDI-II scores of 15.0 compared to 6.8 in AA carriers, supporting the serotonin deficiency hypothesis in depression.

PhD thesis examining genetic and epigenetic factors associated with suicidal behavior in schizophrenia patients. Four studies tested associations between DNA variants (384 SNPs in candidate genes) and suicide attempt/completion, including analysis of CpG methylation sites. Key finding: rs2661319 in RGS4 was significantly associated with suicide attempt (p=0.002) with differential potential methylation levels (55% in attempters vs 65% in non-attempters, p=0.005). However, overall study found limited evidence that genetic or epigenetic factors significantly influence suicide risk in schizophrenia.

Case-control study of 151 Tourette disorder (TD) probands and 858 controls examined SLC6A4 serotonin transporter gene variants. The L allele/L-A haplotype of the 5-HTTLPR/rs25531 promoter locus was overrepresented in TD vs. controls (56.3% vs. 48.8%, OR=1.35, p=0.017). The rare SERT I425V coding variant was found in 1.57% of combined OCD/TD patients (15/956) versus only 0.15% of controls (3/1958), yielding OR=9.0 (χ²=15.03, p<0.0001). All variants were interpreted as gain-of-function alterations of SERT activity, implicating serotonergic dysregulation in Tourette syndrome.

This study examined cortisol responsivity to naloxone challenge (opioid receptor antagonist) in 78 healthy volunteers based on 5-HTTLPR genotypes. Individuals homozygous for the LA allele showed significantly greater cortisol response compared to LS (p=0.005) and SS (p<0.0001) genotype groups. Including the rs25531 SNP in triallelic analysis was more sensitive in detecting genetic differences than biallelic 5-HTTLPR classification alone, suggesting that serotonin transporter variants modulate HPA axis reactivity through interactions with the opioidergic system.

This prospective gene-by-environment study of a university campus shooting found that the 5-HTTLPR multimarker genotype (rs25531 combined with 5-HTTLPR) in the SLC6A4 serotonin transporter gene was significantly associated with acute stress disorder symptoms 2-4 weeks post-trauma in 204 female college students (P=.003 for avoidance symptoms, P=.007 when controlling for exposure). The low-expression s/s, lG/lG, and s/lG genotypes showed higher PTSD symptom scores (mean DEQ=23.91) compared to high-expression genotypes (mean DEQ=18.42).

This study examined the association between the serotonin transporter gene (SLC6A4) triallelic 5-HTTLPR promoter polymorphism and eating problems in 439 college students, finding that women carrying lower-expressing alleles (LG or S) who reported high childhood trauma had significantly elevated eating problem scores (p=0.006). The rs25531 variant was genotyped in combination with 5-HTTLPR to define triallelic genotypes. Main effects showed lower-expressing alleles were associated with higher eating problems overall.

This association study examined the 5-HTTLPR/rs25531 polymorphism in the SLC6A4 gene in 388 combat veterans, finding that the low-expression S'/S' genotype was significantly associated with increased PTSD diagnosis (χ²=16.23, p=5.62×10⁻⁵, OR=1.77) and PTSD severity (r=0.15, p=0.03). The study replicated civilian findings in a military population, demonstrating that each copy of the S' allele conferred a 1.77-fold increased risk of PTSD.

This family-based association study examined parent-of-origin effects and allelic expression imbalance of the serotonin transporter (5HTT) gene in 312 nuclear families with bipolar disorder. The 3'UTR polymorphism G2651T (rs1042173) showed significant association with bipolar disorder (P=0.042), with the T allele being the risk allele (RR=1.346). Analysis of allele-specific mRNA expression in lymphoblastoid cells from 21 bipolar patients (13 suicide attempters, 8 non-attempters) revealed no significant differences in T/G expression ratios between groups, providing no evidence that differential allelic expression or genomic imprinting contributes to suicidal behavior in bipolar disorder.

This candidate gene association study examined the 5-HTTLPR serotonin transporter promoter polymorphism and the rs25531 SNP in relation to attentional bias for negative stimuli in 106 healthy young adults. LA allele homozygotes (L'L') demonstrated a significant bias away from negative word stimuli (M = -6.11 ms, p < 0.05), whereas carriers of the S allele or LG variant (S'L' and S'S' groups) showed no significant attentional bias. The findings support the protective role of the LA allele against negativity bias, a proposed vulnerability marker for depression and anxiety.

Family-based association study of 290 Caucasian families investigating SLC6A4 and ITGB3 genes in autism, stratified by family history. While individual SNPs showed no significant associations after multiple testing correction, stratification by family history revealed nominally significant associations at rs2066713 (SLC6A4) in both positive and negative family history groups, and rs3809865 (ITGB3) in positive family history families. Gene-gene interaction analysis confirmed a significant interaction between rs2066713 (SLC6A4) and rs5918 (ITGB3, Leu33Pro) (p=0.014, survived multiple testing correction), suggesting family history is an important index of genetic heterogeneity in autism susceptibility.

In a large twin sample of 3,243 individuals, the study found no evidence for an interaction between the 5HTTLPR polymorphism (subtyped with rs25531) and stressful life events on risk of depression or suicidality, contradicting the original finding by Caspi et al. (2003). Despite improved genotyping and adequate statistical power, neither 5HTTLPR genotypes nor their interaction with personal or network stressful life events showed significant associations with clinical depression, suicidality, or self-reported depression.

Gene-by-gene-by-environment study of 1,392 African-American participants examining interactions between CRHR1 (rs110402, TCA haplotype) and 5-HTTLPR polymorphisms with childhood abuse on depressive symptoms. Found significant interactions: CRHR1 rs110402 with abuse predicting depression (N=1,059, P=0.0089), and combined 5-HTTLPR and CRHR1 interaction with abuse on depressive symptoms (N=856, P=0.016), suggesting genetic risk alleles in both genes increase depression severity at lower abuse levels.

This case-control association study tested the serotonin transporter polymorphisms 5HTTLPR and rs25531 for association with schizophrenia and neurocognitive phenotypes in 728 schizophrenia cases and 724 controls from the CATIE clinical trial. No significant associations were found for schizophrenia (odds ratio=1.008, p=0.91), neurocognition (p=0.21), working memory (p=0.32), or psychotic symptoms, even in stratified ancestry analyses.

This systematic review of 98 studies examined biological predictors of clozapine response in treatment-resistant schizophrenia patients. Of 379 different gene variants investigated across 70 genetic studies, only three variants (DRD3 Ser9Gly rs6280, HTR2A His452Tyr, and GNB3 C825T) achieved independent replication. Non-genetic predictors included higher prefrontal cortical volumes and lower HVA:5-HIAA ratio in cerebrospinal fluid.

This cross-sectional study of 1,252 individuals (582 European American and 670 African American) found that the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) interacts with childhood adversity and adult traumatic events to increase risk for posttraumatic stress disorder (PTSD). Individuals with the S allele showed significantly increased PTSD risk (triallelic: OR 1.41, 95% CI 1.20-1.66; diallelic: OR 1.60, 95% CI 1.32-1.94, P<0.001) when exposed to stressful life events, providing evidence for gene-by-environment interactions in PTSD etiology.

A targeted re-sequencing study of 382 individuals with Tourette Syndrome investigated four candidate genes (HDC, SLITRK1, BTBD9, SLC6A4) and identified five rare potentially functional variants: one novel HDC coding variant (p.I522L) and four SLITRK1 variants including rs146746846 and rs150504822. Notably, rs150504822 is in linkage disequilibrium with rs6563353, which has been associated with citalopram-induced side effects in depression patients.

Longitudinal study examining the association between the 5-HTTLPR promoter polymorphism (rs25531) in the serotonin transporter gene (SLC6A4) and alcohol consumption in an Estonian population-based cohort (n=1,075). Found a significant genotype×gender×cohort interaction effect on age of first alcohol consumption [F(2,1,063)=7.2, p<0.001], with birth cohort effects modifying the genetic association. Females with s/s genotype showed opposite patterns between older and younger cohorts (late experimenters vs. early experimenters), while males with s/s genotype consistently reported higher alcohol consumption.

A study of 91 Greek patients with schizophrenia and other psychotic disorders examined the association between the 5-HTTLPR polymorphism (rs25531) in the serotonin transporter gene SLC6A4 and clinical symptoms using the PANSS scale, treatment response, and chlorpromazine-equivalent dosages. The LALA genotype showed a trend toward association with reduced medication dosage and lower negative symptom scores (p=0.093 for CPZeq); however, no statistically significant associations were found between HTTLPR genotype and symptom severity or treatment response. A significant gender difference was observed in general psychopathology improvement, with males showing greater improvement than females.

This is an editorial letter discussing functional variation at the SLC6A4 (serotonin transporter) gene, particularly the HTTLPR polymorphism and related SNPs. The authors review evidence that the LG allele (containing rs25531) and rs25532 alter SLC6A4 expression levels, with rs25532 T allele decreasing luciferase reporter gene expression by 15-30% in S constructs and 25-80% in LA constructs across different cell lines.

A systematic review of 98 studies investigating biological predictors of clozapine response in treatment-resistant schizophrenia. Of 70 genetic studies examining 379 variants, only three genetic variants have independently replicated findings: DRD3 Ser9Gly (rs6280), HTR2A His452Tyr, and GNB3 C825T (rs5442/rs5443). Non-genetic predictors include higher prefrontal cortical structural integrity and activity, and lower HVA:5-HIAA ratio in cerebrospinal fluid.

A comprehensive review of the genetic basis of aggressive behavior, covering candidate genes in neurotransmitter systems (TPH1, TPH2, SLC6A4, DRD4, COMT, MAOA), hypothalamic-pituitary genes (OXT, OXTR, AVPR1A, AVPR1B), and GWAS findings (LRRTM4 rs11126630 p=5.30×10⁻⁸, CDH13 rs11649622 p=4.19×10⁻⁶, FYN rs2148710 p=2.9×10⁻⁸, DYRK1A). The review concludes that genetic predisposition to aggressive behavior involves multiple genes with small individual effects (1-2% each).

This case-control study of 75 stroke survivors with post-stroke depression (PSD) and 75 non-depressed stroke survivors examined associations between serotonin transporter (SERT) gene polymorphisms and PSD. The 5-HTTLPR s/s genotype conferred 3.1-fold increased odds for PSD (95% CI 1.2-8.3), and STin2 VNTR 9/12 or 12/12 genotypes conferred 4.1-fold increased odds (95% CI 1.2-13.6), while rs25531 showed no significant association.

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.