Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD

• Published in: Science translational medicine 2011-08, Vol.3 (95), p.95ra75-95ra75
• Main Authors: Lionel, Anath C, Crosbie, Jennifer, Barbosa, Nicole, Goodale, Tara, Thiruvahindrapuram, Bhooma, Rickaby, Jessica, Gazzellone, Matthew, Carson, Andrew R, Howe, Jennifer L, Wang, Zhuozhi, Wei, John, Stewart, Alexandre F R, Roberts, Robert, McPherson, Ruth, Fiebig, Andreas, Franke, Andre, Schreiber, Stefan, Zwaigenbaum, Lonnie, Fernandez, Bridget A, Roberts, Wendy, Arnold, Paul D, Szatmari, Peter, Marshall, Christian R, Schachar, Russell, Scherer, Stephen W
• Format: Article
• Language: English
• Subjects: Adolescent; Attention Deficit Disorder with Hyperactivity - genetics; Autistic Disorder - genetics; Case-Control Studies; Child; Child, Preschool; DNA Copy Number Variations - genetics; Female; Genetic Loci - genetics; Genetic Predisposition to Disease; Glycoproteins - genetics; Humans; Male; Nervous System Diseases - genetics; Pedigree; Risk Factors; Sequence Analysis, DNA; Transcription Factors - genetics; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.3002464

Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.