rs165774

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.

A two-stage Japanese case-control study investigating the association of COMT gene SNPs and copy number variants (CNVs) with schizophrenia. Stage 1 included 513 schizophrenia patients and 705 controls; stage 2 replicated findings in 1,854 patients and 2,137 controls. The intronic SNP rs165774 and promoter region CNV6, exon CNV8, and CNV9 showed strong associations with schizophrenia in stage 1. In stage 2 replication, rs165774, CNV6, and CNV8 maintained significant associations, suggesting that low-frequency CNVs and small CNVs (<30 kb) in COMT are genetic risk factors for schizophrenia.

This population-based study of 4,470 breast cancer cases from the SEARCH cohort examined associations between germline polymorphisms in 6 steroid hormone metabolism genes (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival after breast cancer diagnosis. A COMT polymorphism (rs4818) showed significant association with survival in a dominant model (HR=0.80, 95% CI: 0.69-0.95, p=0.009), though this was only marginally significant after permutation adjustment (p=0.047). No significant associations were found in the other genes studied.

This case-control association study of 650 German migraine with aura (MA) patients and 650 controls tested 53 variants across 10 dopaminergic system genes. Three SNPs in the dopamine-beta hydroxylase (DBH), dopamine transporter (SLC6A3), and dopamine D2 receptor (DRD2) genes showed significant associations with MA. After gene-wide correction, rs2097629 in DBH (OR=0.77, p=0.0012) and rs40184 in SLC6A3 (OR=0.81, p=0.0082) remained significant, with supporting evidence from 2,937 British controls. These findings provide genetic evidence for dopaminergic system involvement in MA pathogenesis.

This family-based association study investigated four ADHD candidate genes (COMT, SLC6A2, MAOA, SLC6A4) for sexually dimorphic genetic effects in 474 ADHD-affected offspring. The Met allele of COMT Val158Met showed stronger association in males (OR=1.42, p=0.003) but not females (p=0.936), and when combined with prior data showed significant gender effects (p=0.007). SLC6A2 and MAOA also showed sex-stratified associations, supporting the hypothesis that ADHD risk genes have sexually dimorphic effects.

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.