Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

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.

Figure 1

FISH validation of the GRM5 CNV. Metaphase spreads from (a) the non-affected father and (b) an ADHD patient with the deletion hybridized with probes labeled with Spectrum red (red signal) or Spectrum green (green signal). FISH was performed using fosmid W12-2219g4 (red signal) specific for the GRM5 deletion and BAC RP11-697e14, a control probe for the subtelomeric region of chromosome 11q (green signal). A portion of the GRM5 gene, including the 82kb region deleted in this family, is part of a 325kb segmental duplication present in two copies on chromosome 11, one in 11q and the other in 11p. This results in the observation of two red signals for the GRM5 probe in the non-deleted father (a), on both homologs of chromosome 11 indicated by white arrowheads. The annotated GRM5 gene in the reference genome is present on 11q. In the deleted patient (b), the red signal on 11q is missing on one of the two chromosome 11 homologs, because of the deletion within the GRM5 gene, (indicated by a blue arrowhead).