rs3785157

A twin study of 1,312 children investigating genetic mediation of endophenotypes in ADHD. Using candidate gene SNPs from dopaminergic, noradrenergic, and serotonergic pathways, the study found the strongest association between rs7984966 in HTR2A and reaction time variability (P=0.007), and rs3785157 in SLC6A2 with commission errors. Mediation analyses revealed that commission errors mediated 38% of the SLC6A2-inattention association, and reaction time variability mediated 44% of the HTR2A-inattention association, suggesting these cognitive measures are intermediate phenotypes on the genetic pathway to ADHD.

High-density SNP mapping of 14 noradrenergic genes in 270 ADHD families (810 individuals from Ireland and Australia) revealed suggestive single-SNP associations but significant haplotype associations in SLC6A2 (5-SNP haplotype: rs36009, rs1800887, rs8049681, rs2242447, rs9930182; χ²=9.39, p=0.019, OR=1.51) and ADRA1B (6-SNP haplotype: rs2030373, rs6884105, rs756275, rs6892282, rs6888306, rs13162302; χ²=7.79, p=0.042, OR=2.74). Notable single-SNP findings included rs8047672 in SLC6A2 (χ²=7.21, p=0.007, OR=2.04) and rs6888306 in ADRA1B (χ²=5.95, p=0.014, OR=1.46), supporting a role of the noradrenergic pathway in ADHD genetic risk.

This replication study tested association of two SNPs in the noradrenaline transporter gene (SLC6A2) with ADHD across four independent datasets (IMAGE ST2, Dublin, and MGH samples). rs11568324 showed consistent evidence for a rare protective T allele (OR=0.33-0.34 across datasets, combined P=8×10⁻⁵), while rs3785143 showed weaker and inconsistent association (combined P=0.008, OR=1.3). The rare T allele of rs11568324 (MAF~1%) appears to confer protection against ADHD, though clinical relevance is limited due to its rarity.

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 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.