W64. family based association and linkage analyses of familial adhd

ADHD is a highly heritable childhood disorder, with estimated h2 of 0.7. To characterize the genetic variants contributing to this heritability, we used family-based designs, studying families with many members affected by ADHD. Genome-wide SNP array data were obtained on two family cohorts: (1) NHGRI family cohort (359 nuclear families,1538 individuals); (2) NCR family cohort (25 extended and 132 nuclear families, 631 members). Family-based association tests (FBAT) were used to identify variants shared across affected individuals in all families, while linkage analyses were used to identify shared haplotypes and variants with potentially larger effects. Using neuroimaging data from the NCR families, we asked if genes associated with familial ADHD overlapped with genes associated with neural features. A meta-analysis of FBAT identified three genome-wide significant SNP associations that lay upstream from TFRC, intronic to TRIM31 and intronic to DFNA5. TRIM31 has been found associated to intelligence in individuals with ADHD, while variants in DFNA5 have been identified as pleiotropic loci associated with multiple psychiatric disorders. Genes associated with ADHD (at p2) and one significant linkage region (LOD > 3) on 19p13.2-13.11. The linkage region on 19p encompassed a genome-wide significant variant found in the FBAT of the NHGRI families (rs55741253, p=2.68 × 10-8). Additionally, two linkage regions that reached a LOD > 2 in our meta-analysis replicated significant linkages from prior studies. Genes associated with a feature of the brain's functional connectivity, capturing the interaction between the brain's default mode and task positive network, overlapped with genes associated with ADHD (p=0.04). Using family-based association methods, we report significant associations between three genes and familial ADHD, with one signal lying within a region of significant linkage.