rs4633

A candidate gene association study of dementia risk in 2,857 older postmenopausal women from the Women's Health Initiative Memory Study examining 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, KIBRA). The APOE/TOMM40 locus showed the strongest association (rs157582: OR=1.64, p=2.4×10⁻⁸ for probable dementia), with additional significant associations in COMT (rs737865), BDNF (rs1491850), and KIBRA (rs4320284, rs2241368, rs244904). Results support APOE/TOMM40 as a dementia risk locus and extend associations to COMT, BDNF, and KIBRA genes.

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 case-control study of 468 schizophrenia patients treated with clozapine (202 with metabolic syndrome, 266 without) examined associations between three COMT gene polymorphisms (rs4633, rs4680, rs4818) and metabolic parameters. The key finding was a significant association between rs4680 (the Val158Met variant) and elevated triglyceride (TG) levels (corrected P=0.024), particularly among female patients (P=0.009), suggesting a potential role for COMT variation in clozapine-associated metabolic syndrome.

A candidate gene association study in 100 Russian vitiligo patients and 100 controls identified a strong novel association between GSTP1 rs1138272 (Ala114Val, OR=13.03, Bonferroni-adjusted P=0.0015) and vitiligo susceptibility. Cumulative analysis of multiple xenobiotic metabolizing genes showed that carrying higher numbers of risk alleles was associated with increased vitiligo risk (9-16 vs 3-8 alleles: OR=2.79, P=0.00063), supporting a polygenic model for vitiligo involving detoxification pathway genes.

Case-control study of 112 Brazilian fibromyalgia patients and 110 healthy controls examining COMT gene SNPs rs4680 and rs4818. The homozygous mutant genotype AA of rs4680 was present in 77.67% of patients vs 28.18% of controls (FIQ score 87.92 vs 15.56). The CC genotype of rs4818 was found in 73.21% of patients vs 39.09% of controls (FIQ score 86.14 vs 13.13). Both SNPs showed significant association with fibromyalgia and elevated pain sensitivity (p < 0.001).

This population-based study of 3,904 subjects examined the interaction between COMT and TXNRD2 SNPs and temporomandibular disorder (TMD) pain, modified by depressive symptoms. Six SNPs from the first COMT/TXNRD2 haploblock showed significant interactions with depressive symptoms (smallest p-value: 2.7 × 10^-10), with opposite SNP effects between depressed and non-depressed individuals. In non-depressed subjects, rs5993882 (COMT) was most associated with TMD pain, while in depressed subjects, rs1544325 (COMT) and TXNRD2 SNPs were preferentially associated. The findings indicate that COMT polymorphisms affect pain perception through a mechanism significantly moderated by depressive symptoms.

This candidate gene association study examined 14 SNPs in ADRB2 and COMT genes in 1,004 Western Australian adolescents (age 17) to identify genetic variants associated with chronic musculoskeletal complaints. Of the SNPs tested, only rs2053044 in ADRB2 (recessive model) showed association with chronic disabling neck and low back pain (OR = 2.49; 95% CI = 1.25-4.98; p = 0.01) and pain in 3-4 body areas (OR = 1.86; 95% CI = 1.13-3.06; p = 0.02). The findings suggest that genetic variants in ADRB2 may be involved in regulating chronic musculoskeletal pain in adolescents.

Case-control study of 604 Han Chinese examining associations between two COMT gene polymorphisms (rs740603 and rs4818) and schizophrenia. Found no significant association with schizophrenia susceptibility, but rs740603 and the rs740603(G)-rs4818(G) haplotype were associated with negative symptoms severity, particularly in females (p=0.025 for rs740603; p=0.021 for haplotype in females).

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 review examines polymorphisms in six genes (SCN9A, KCNS1, GCH1, COMT, OPRM1, OPRK1) involved in nociception and their associations with chronic post-surgical pain (CPSP). Key findings include rs4680 in COMT associated with higher pain risk (OR 3.42 in knee replacement patients), rs734784 in KCNS1 explaining ~5% of pain variance in lumbar discectomy patients, and rs6746030 in SCN9A conferring increased pain sensitivity. The paper reviews conflicting evidence across multiple surgical populations and discusses potential clinical applications of genetic testing for CPSP risk stratification.

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 comprehensive review synthesizes genomic and pharmacogenomic research in schizophrenia, discussing over 200 candidate genes associated with psychotic disorders, genetic mechanisms including copy number variants and microRNA alterations, and pharmacogenomic factors affecting antipsychotic efficacy and safety. Key genes covered include dopamine receptors (DRD1-5), dysbindin (DTNBP1), DISC1, neurotrophic factors, and metabolic enzymes such as CYP2D6, CYP3A4, and COMT, with emphasis on genotype-phenotype correlations in antipsychotic response and side effects.

Association study of COMT haplotypes in 435 adult ADHD patients and 383 controls reveals that the high-activity COMT haplotype (tagged by rs6269) is associated with increased hyperactivity/impulsivity scores (P=0.01). All four COMT SNPs (rs6269, rs4633, rs4818, rs4680) showed a trend toward association with the hyperactivity/impulsivity dimension (peak P=0.007 for rs6269), suggesting COMT haplotype variation has stronger effects on ADHD symptom severity than the Val158Met polymorphism alone.

Literature review of 77 publications examining the effects of genes COMT, MAO-A, MAO-B, DAT, DRD2, VMAT2, TPH2, and SNCA on Parkinson's disease neuropsychiatric symptoms and therapy response. Key polymorphisms include rs1800497 (DRD2) associated with impulse control disorders, rs6269/rs4633/rs4818/rs4680 (COMT) with cognitive decline, and rs1352250/rs6582078 (TPH2) with impulse control. The review identifies genetic predictors for early complications (cognitive decline, depression, psychosis, impulse control disorders) and therapy optimization, relevant for patient selection for deep brain stimulation.

This case-control study examined COMT gene polymorphisms in 150 endometrial cancer patients and 165 controls, identifying that the COMT codon 62 T/T genotype (rs4633) is associated with increased endometrial cancer risk (OR=2.39, 95% CI: 1.31-4.37, P=0.004). The protective C-G haplotype of codons 62 and 158 was significantly more frequent in controls (P<0.0001), and immunohistochemistry showed that polymorphic variants led to lower COMT protein expression in cancer tissues.

This association study examined 28 SNPs across 14 dopamine pathway candidate genes in 403 families with autism to test the hypothesis that common genetic variation in dopamine metabolism contributes to autism susceptibility. While rs2239535 (YWHAB, chromosome 20) showed the strongest nominally significant association (p=0.008), this did not remain significant after correction for multiple comparisons, and no significant gene-gene interactions were detected using Multifactor Dimensionality Reduction analysis.

Population genetics study of OPRM1 and COMT gene variants in the Chaco province of Argentina. Genotyped 11 SNPs in 54 individuals from Misión Nueva Pompeya and compared with published data from Resistencia (n=109) and Wichí native communities (n=27). Found significant population differentiation at Fst values ranging from 1.507% to 2.744% between populations, with notable variation in pain-related and dopaminergic genes that could inform personalized pain management strategies.

A case-control study of 320 Korean schizophrenic patients and 379 controls found that the rs6267 (Ala72Ser) polymorphism in the COMT gene is associated with increased schizophrenia risk (adjusted OR=1.82, 95% CI=1.19-2.76; P=0.005), with a stronger effect in females (OR=1.93; P=0.018). The 72Ser allele was correlated with reduced COMT enzyme activity in red blood cells. In contrast, the commonly studied Val158Met polymorphism (rs4680) showed no significant association with schizophrenia in this Korean population.

This functional study examined differential allele expression of COMT polymorphisms using an RT-coupled 5' nuclease assay in human lymphoblasts and brain tissue. The Met158 allele (rs4680) showed consistent 65-77% higher mRNA expression than Val158 across both tissue types (29/29 lymphoblasts and 39/39 brain samples). Val158 was less expressed despite being associated with higher enzyme activity, demonstrating opposing effects on mRNA expression versus protein activity that together result in ~30% lower enzyme activity with the Met158 allele.

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.