rs737865

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.

Meta-analysis of 20 case-control studies examining the association between COMT gene rs165599 SNP and schizophrenia. Found no statistically significant overall association under four genetic models (OR ranged 0.955-0.985), though sex-specific analysis showed G allele carriers had increased schizophrenia risk in females (OR=1.366, 95% CI=1.094-1.706) compared to AA homozygotes.

A case-control study of 576 fetuses/newborns with neural tube defects (NTDs) and 594 controls in a Chinese population examined MTHFR and COMT gene variants. The MTHFR rs1801133 TT genotype was associated with increased NTD risk (OR=1.37), and a synergistic interaction between COMT rs737865 CC and MTHFR rs1801133 TT genotypes showed over 3-fold increased risk for NTDs (OR=3.02) and anencephaly (OR=3.39), suggesting these variants interact to modulate folate metabolism and increase birth defect susceptibility.

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 case-control and family-based study evaluated 64 SNPs in 34 genes for associations with spina bifida in 558 Irish case-families and 994 controls. Spina bifida was significantly associated with LEPR rs1805134 (GRR: 1.5, P = 0.0264) and COMT rs737865 (GRR: 1.4, P = 0.0206), with additional confirmations of previous findings in MTHFR 677C>T and other genes, suggesting roles for leptin signaling and methylation pathways in neural tube defect pathogenesis.

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 association study examines COMT polymorphisms and cocaine-induced paranoia (CIP) in European-American and African-American populations. The nonsynonymous Val158Met variant (rs4680) and three additional SNPs (rs933271, rs5993883, rs740603) were identified as potentially functional. Family-based and case-control analyses revealed significant haplotype associations with CIP, particularly haplotype A-A-T in both European-American families and unrelated African-American individuals, supporting COMT's role in dopamine/norepinephrine metabolism affecting cocaine-induced psychiatric symptoms.

This study investigated 12 genetic polymorphisms in four dopamine-related genes (COMT, MAOA, MAOB, and DBH) in 179 incarcerated male Russian adolescents and 242 matched controls to identify genetic associations with aggressive behavior and conduct disorder. The authors found that while individual genetic variants did not differentiate groups, specific combinations of variants (haplotypes) and interactions between variants within and across genes produced informative classifications for incarceration status (P < 0.0001, Nagelkerke R² = 0.141) and conduct disorder diagnosis (P < 0.0001, Nagelkerke R² = 0.158), with a 4-marker model involving COMT rs737865, COMT rs165599, DBH rs1611115, and DBH rs739398 being most predictive.

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.

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 family-based association study investigated three COMT SNPs (rs737865, rs4680 Val158Met, rs165599) in 2,045 individuals from 987 Australian families for association with anxiety disorders, depression, and neuroticism. The study found no significant evidence for association between any COMT variant and anxiety, depression, or neuroticism either in the total sample or when stratified by sex. Only a weak haplotype association was observed (T-G-G haplotype with panic disorder/agoraphobia, P=0.042 before multiple testing correction).

A case-control study of 241 Chinese schizophrenia patients and 290 controls failed to replicate the Shifman et al. haplotype (rs737865-rs4680-rs165599) association with schizophrenia, finding no significant associations at allelic, genotypic, or haplotypic levels (P > 0.05). Though the G-G-G haplotype showed a modest risk effect (OR = 1.277, 95% CI = 0.883–1.848, P = 0.193), the result was not statistically significant, suggesting ethnic differences in COMT variant effects.

This dissertation investigated the genetic basis of violent criminal behavior, antisocial personality disorder (ASPD), and broader antisocial behavior through GWAS and meta-analyses in Finnish and international populations. Study I identified an intronic CDH13 variant (rs11649622, OR=2.7, p=4.19×10⁻⁶) associated with extremely violent offending, replicated in homicide offenders (p=5.3×10⁻⁷, OR=2.17). Study II revealed the first genome-wide significant association between LINC00951 variant rs4714329 (OR=1.59, p=1.6×10⁻⁹) and ASPD. Study III meta-analysis of 16,400 individuals found no genome-wide significant associations with broader antisocial behavior, though polygenic risk scores explained ~5% of phenotypic variance.

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.