1. ¹Department of Child and Adolescent Psychiatry, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
2. ²Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
3. ³Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
4. ⁴Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
5. ⁵Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
6. ⁶Joseph Stokes Jr Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
7. ⁷Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
8. ⁸Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
9. ⁹Dipartimento di Medicina Sperimentale, University La Sapienza, Rome, Italy
10. ¹⁰Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
11. ¹¹Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

Correspondence: Dr H Hakonarson, Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Rm 1216E ARC, Philadelphia, PA 19104-4318, USA. E-mail: hakonarson@chop.edu; Dr PS White, Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Rm 1407 CHOP North, Philadelphia, PA 19104-4318, USA. E-mail: white@genome.chop.edu

¹²These authors contributed equally to this work.

Received 4 December 2008; Revised 8 May 2009; Accepted 26 May 2009; Published online 23 June 2009.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.