rs165599

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.

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 paper presents CalPen, a web-based tool for calculating penetrance (disease likelihood given a mutation) in complex genetic disorders. The authors validated CalPen against published penetrance calculations for schizophrenia-associated copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). They analyzed 15 CNVs in 39,059 schizophrenia patients and 55,084 controls (average penetrance 7%, ranging from ~1.4% for 15q11.2 deletions to ~20% for 22q11.21 CNVs) and 145 SNPs in 45,405 patients and 122,761 controls (average penetrance 0.7%, with rs1801028 showing the highest at 1.6%).

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 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 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 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.

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 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.

Case-control and family-based association study in 1,794 individuals (296 cases, 370 controls, and 296 families in NIMH sibling study; 501 cases and 627 controls in German sample) investigating statistical epistasis between COMT polymorphisms (rs2097603, rs4680/Val158Met, rs165599) and SNPs in candidate schizophrenia genes. Found significant gene-gene interactions: three RGS4 SNPs showed increased schizophrenia risk with COMT (LRT P-values 0.02-0.05), six G72/DAOA SNPs exhibited epistasis with COMT, three GRM3 SNPs showed interaction effects, and DISC1 SNPs interacted with COMT Val158Met. Main effects for most candidate genes were null, highlighting the importance of epistatic models in psychiatric genetics.

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.