Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ⩽1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10−4 after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756–162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10−3 after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10−2). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Genetics of attention deficit hyperactivity disorder

“…A study of 489 ADHD patients and 1285 controls found rare CNVs in the parkinson protein two gene (PARK2) [123]. The result was significant after empirical correction for genome-wide testing.…”

“…Because CNVs often delete or duplicate a large genomic segment spanning part of a gene or even entire genes, they often have clear implications for gene functioning. Studies of CNVs in ADHD assessed ADHD youth and controls for the presence of large (>500 kb), rare CNVs [77,[122][123][124][125][126][127]. Each study, except one, found an odds ratio greater than one, indicating a greater burden of large, rare CNVs among ADHD patients compared with controls.…”

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

“…A threefold excess of duplications and deletions has been observed in SZ cases (table 7),31 46 and both rearrangements have been implicated in ADHD 48 103…”

“…48 103 Among them, the nuclear distribution gene E homologue 1 ( NDE1 ) is of particular interest, because the nudE neurodevelopment protein 1 is essential for mitosis and neurodevelopment, and interacts with the disrupted in SZ 1 protein,105 implicated in SZ and in other major psychiatric disorders 106–108 . NDE1 deficiency impairs neurogenesis, by causing profound neuronal proliferation defects and a deficiency in cortical lamination, as observed in Nde1-null mice and in patients with NDE1 homozygous mutations, who present extreme microcephaly with lissencephaly 106 107.…”

New Insights into the Pathogenesis and Pharmacogenomics of Attention Deficit Hyperactivity Disorder

“…To identify rare (frequency ≤ 1%) CNVs that increase the risk of ADHD, Jarick et al [23] performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, they observed a nonsignificant 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases and rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls.…”