rs3785143

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 study examined 11 SLC6A2 gene SNPs in 159 healthy Caucasian volunteers using a double-blind crossover design with placebo and D-amphetamine (10 and 20 mg). SNPs rs36017 and rs1861647 were significantly associated with higher ratings of elation and vigor after 20 mg D-amphetamine, with p-values of 0.033 and 0.002 respectively. Haplotype blocks also showed significant associations with vigor responses.

Analysis of 554 SNPs across 47 candidate genes in 590 families from the IMAGE ADHD genetics study found no overall parent-of-origin effect (χ² = 1.82, P = 0.117) for ADHD transmission. Five SNP markers in DDC, TPH2, and SLC6A2 showed nominal associations (P < 0.01) with ADHD combined subtype when restricted to maternal or paternal transmission only, but these findings likely represent false positives given multiple comparisons.

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.

Haplotype-tagging SNP analysis in 364 individuals from 152 ADHD families identified significant associations between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596) and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are valid ADHD endophenotypes linked to dopaminergic and noradrenergic pathways.

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 review of molecular genetic studies of ADHD in Han Chinese populations summarizes candidate gene studies across dopaminergic, noradrenergic, serotonergic, and enzymatic systems, along with the first GWAS in Chinese ADHD cases (n=1040) and controls (n=963). While no single gene has been definitively identified, significant associations include DRD4 7-repeat allele (OR=1.70, 95% CI 1.20-2.40, p=0.003 in males), DBH rs2519152, and various polymorphisms in COMT, NET1, and serotonin genes, though results remain inconsistent across studies.

This genome-wide association study examined methylphenidate response in 187 children with ADHD using 319,722 SNPs. The most significant association was at P=3×10⁻⁶ (rs9627183 and rs11134178), falling short of genome-wide significance. Two SNPs in the norepinephrine transporter gene (NET/SLC6A2) showed suggestive evidence (rs17841329 and rs192303, P<0.01), while the metabotropic glutamate receptor 7 gene (GRM7, rs3792452) showed the most intriguing association (P=2.6×10⁻⁵), implicating noradrenergic and glutaminergic pathways in methylphenidate response.

This review examines molecular genetic studies of attention-deficit hyperactivity disorder (ADHD) in Han Chinese samples, including candidate gene studies, endophenotype research, genome-wide association studies, and pharmacogenomic investigations. Eight GWAS conducted for ADHD have been inconclusive with no genome-wide significant associations identified, though candidate gene studies have identified associations with dopaminergic (DAT1, DRD4, DRD2, DRD3), noradrenergic (NET1, ADRA2A, ADRA2C), serotonergic (SLC6A4, HTR genes), and metabolic pathway genes (COMT, MAOA, MAOB, DBH, TPH). A meta-analysis of DRD4 longer repeats showed OR=1.70-1.74 in males with ADHD-C subtype.