rs6313

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 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 dissertation examined pharmacogenetic associations with clozapine adverse effects in 237 Finnish schizophrenia patients. ADRA2A rs1800544 was associated with clozapine-induced sialorrhea (OR 2.13, 95% CI: 1.17-3.88, p=0.013). Eight HNMT SNPs in complete linkage disequilibrium (r²=1) were associated with sedation. CHRM3 rs685548 and weighted genetic risk scores from HTR4, HTR7, TPH1, CHRM2, ABCB1, and OPRM1 were associated with anticholinergic symptoms.

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.

Association study of 55 SNPs in 887 Hungarian adults examining genetic predisposition to aggression measured by the Buss-Perry Aggression Questionnaire. The HTR2A rs7322347 intronic variant showed significant association with aggression after Bonferroni correction (p = 0.0007), with carriers of the minor A allele showing lower aggression levels. The DRD4 rs916455 variant also showed nominal significance (p = 0.0275) but did not survive multiple testing correction.

Large candidate gene association study of fibromyalgia identifying genetic risk factors across 350 genes involved in nociception, inflammation, and mood. Discovery phase (496 FM patients, 348 controls) found significant associations for GABRB3 (rs4906902, p=3.65×10⁻⁶, OR=0.46), TAAR1 (rs8192619, p=1.11×10⁻⁵, OR=3.8), and GBP1 (rs7911, p=1.06×10⁻⁴, OR=1.7). Replication phase (1004 FM cases, 3725 controls) confirmed association for TAAR1, RGS4, CNR1, and GRIA4 genes, suggesting multiple biological pathways underlying fibromyalgia susceptibility.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).

This study examined the rs6313 (T102C) polymorphism in the 5-hydroxytryptamine receptor 2A gene (5HTR2A) in 213 Taiwanese children (116 with nocturnal enuresis and 97 controls). While no significant association was found between rs6313 and nocturnal enuresis overall, the study identified a significant association with polysymptomatic nocturnal enuresis: the TT genotype showed an odds ratio of 10.71 (95% CI 2.66-43.12) and the T allele had an OR of 3.7 (95% CI 2.01-6.79, P=0.000015) compared to the CC genotype and C allele, respectively.

This review chapter synthesizes genetic research on suicidal behavior, covering family, twin, and adoption studies demonstrating ~45% heritability. It highlights key serotonergic genes (TPH1, TPH2, 5-HTT, 5HTR1A, 5HTR2A) associated with suicide risk, dopaminergic pathway genes (DRD2, COMT Val158Met showing increased risk), BDNF (reduced levels in suicide victims), and genome-wide linkage studies identifying suicide risk loci on chromosomes 2p, 5q, 6q, 8p, 11q, and Xq. The review concludes that serotonergic candidates represent the most credible evidence for genetic susceptibility to suicide.

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 comprehensive review examines the pharmacogenetics of antipsychotic drug treatment, synthesizing evidence on how genetic variations influence both treatment efficacy and adverse effects. Key findings show dopamine receptor genes (DRD2, DRD3) predominantly associated with positive symptom response, while serotonin genes (HTR1A, HTR2A, HTR2C) associate with negative symptom improvement. For weight gain, the HTR2C promoter polymorphism (-759 C/T) shows strong protective effects (relative risk 3.45) in risperidone/olanzapine treatment. Tardive dyskinesia associations involve multiple genes including DRD2, DRD3, HTR2A, HTR2C, and SOD2, though GWAS findings often diverge from candidate gene results.

Meta-analytic review of candidate gene studies for childhood ADHD examining 19 genes. Significant associations identified for DAT1 (3' UTR VNTR: OR=1.12, p=0.028; rs27072: OR=1.20, p=0.006), DRD4 (exon 3 VNTR: OR=1.33, p=0.00007; rs1800955: OR=1.21, p=0.007), DRD5, 5HTT, HTR1B (rs6296: OR=1.11, p=0.010), and SNAP25 (rs3746544: OR=1.15, p=0.030).

This is a comprehensive literature review of candidate genes and their single nucleotide variants associated with antipsychotic-induced tardive dyskinesia in schizophrenia patients. The review examined genes involved in dopamine system (DRD1, DRD2, DRD3), catecholamine metabolism (COMT), serotonin system (HTR2A, HTR2C), and other pharmacodynamic and pharmacokinetic pathways. Timely identification of genetic variants in these genes could contribute to developing diagnostic tests and selecting safer antipsychotic therapy.

A family-based association study of 12 SNPs in the HTR2A serotonin receptor gene in 1,408 Irish subjects from 270 high-density schizophrenia families (755 with psychotic illness, 127 with suicidal ideation). Testing for association with psychosis and suicidal ideation using FBAT and PDTPHASE, the authors found two SNPs reaching nominal significance in psychosis (rs659734 p=.05 in FBAT, rs2070037 p=.05 in PDTPHASE) and several haplotypes with modest association (p=.02 to .04), but no significant associations in the suicidal ideation subset and no surviving multiple testing correction. The study does not provide support for HTR2A as a susceptibility gene for psychotic illness or suicidal ideation.

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.

This study investigated whether HTR2A A-1438G/T102C polymorphisms (rs6311/rs6313) predict aripiprazole treatment response in 128 Han Chinese schizophrenia patients. The GG/CC genotype group predicted poor negative symptom response (PANSS negative score 3.93 points higher in GG/CC vs. AA/TT, P=0.007), with clinical factors like medication dosage and age also significantly influencing treatment outcomes.

Case-control study investigating associations between three SNP polymorphisms (COMT rs4680, 5-HT2A rs6313, rs6311) and fibromyalgia syndrome susceptibility in 80 FMS patients and 91 controls. No significant differences were observed in allele or genotype frequencies between patients and controls for any of the three polymorphisms (all P > 0.05), suggesting these variants are not susceptibility factors for FMS.

This association study examined epistatic interactions among seven serotonin pathway genes in autism etiology using 186 autistic families and 181 controls. The authors found a significant main effect of HTR5A rs1800883 (P = 0.0088), and identified a significant three-locus epistatic interaction between SLC6A4 intron 2 VNTR and ITGB3 rs5918 with additive HTR5A rs6320 effects (P < 0.001) associated with autism risk. Additionally, ITGB3 haplotypes showed association with platelet serotonin levels (P = 0.0163), supporting a common genetic mechanism linking gene interactions to both autism susceptibility and hyperserotonemia.

A case-control study of 51 children with obsessive-compulsive disorder (OCD) and 51 healthy controls found that serum BDNF and GSK-3β levels were statistically significantly higher in the OCD group compared to controls. No significant differences were detected in IL-6, hs-CRP, or β-catenin levels. The study suggests that BDNF and GSK-3β may serve as neuroinflammatory markers in childhood OCD.

A case-control study (N=99: 49 patients with major depressive disorder, 50 controls) conducted in Mexican mestizo population analyzing 8 genetic variants in serotonin and dopamine receptors (HTR1A rs6295, HTR2A rs6311/rs6313/rs6314, HTR6 rs1805054, DRD2 rs1801028/rs1800497, DRD3 rs6280) using PCR-RFLP genotyping. The study characterized genotype and allele frequencies in depressed patients versus healthy controls and evaluated associations with antidepressant treatment response using Hamilton Depression Scale.

This association study examined 20 polymorphisms from 12 candidate genes in 163 ADHD probands and 129 controls, finding significant associations with two genes: NET1 (rs998424 P=0.009, rs3785157 P=0.002) and DRD1 (rs4532 OR=1.63 P=0.006, rs265981 OR=1.61 P=0.008). The study used both family-based transmission disequilibrium tests and case-control analyses. No significant effects were detected on cognitive, behavioral, or brain MRI measurements.

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.