The genetic overlap between lntellectual Disability and Attention-Deficit/Hyperactivity Disorder
Objective: Attention-Deficit/Hyperactivity Disorder (ADHD) and lntellectual Disability (ID) co-occur more aften than expected by chance, suggesting some genetic overlap. In four subprojects we investigated whether genes, affected by rare genetic variations in patients with ID, contribute to multifactorial ADHD. Methods: (1) Single nucleotide polymorphisms (SNPs) in 392 autosomal ID-related genes and (2) a subset involved in neurite outgrowth were tested for association with multifactorial ADHD risk, bath on gene-set and gene-wide level, using data from the meta-analysis of the ADHD working group of the Psychiatrie Genomic Consortium (PGC; 5,621 cases and 13,589 controls). (3) Twelve genes selected on frequent occurrence in copy number variants (CNVs) in patients with ADHD and ID and/or congenital anomalies (PRODH, RBFOXl, PTPRD, CNTNAP2, NRXNl, XYL Tl, PRIM2, FAM110C, SKI, NRG3, GRIN2A, NRG3 and ERBB4) and (4) two genes selected because of suggested involvement in ID and ADHD in the literature (CHRNAl and NRXNl) were tested for gene-wide associations with multifactorial ADHD risk using the ADHD PGC meta-analysis data and with symptom counts using data from the International Multicenter ADHD Genetics project (IMAGE; 930 cases). Single-SNP and gene-wide association analyses for CHRNAl and NRXNl were performed with regional brain volumes in 1302 healthy participants of the Bra in lmaging Genetics (BIG) cohort. Single-SNP association analyses were also performed for voxel-wide structural connectivity measurements. Results: SNPs in all autosomal ID-related genes, but not in the subset of neurite outgrowth genes, were significantly linked to ADHD as a group. The MEF2C gene showed gene-wide association with ADHD risk. Other gene-wide and SNP-specific analyses did not yield significant associations. Conclusion: SNPs in 392 genes, and specifically the MEF2C gene, affected by rare genetic variations in patients with ID, contribute to multifactorial ADHD risk as a group. This contribution to ADHD risk does not seem to be driven by neurite outgrowth genes.
Faculteit der Sociale Wetenschappen