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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.

SUBMITTER: Jarick I

PROVIDER: S-EPMC3873032 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Jarick I I Volckmar A-L AL Pütter C C Pechlivanis S S Nguyen T T TT Dauvermann M R MR Beck S S Albayrak Ö Ö Scherag S S Gilsbach S S Cichon S S Hoffmann P P Degenhardt F F Nöthen M M MM Schreiber S S Wichmann H-E HE Jöckel K-H KH Heinrich J J Tiesler C M T CM Faraone S V SV Walitza S S Sinzig J J Freitag C C Meyer J J Herpertz-Dahlmann B B Lehmkuhl G G Renner T J TJ Warnke A A Romanos M M Lesch K-P KP Reif A A Schimmelmann B G BG Hebebrand J J Scherag A A Hinney A A

Molecular psychiatry 20121120 1

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 popu ...[more]

PMID: 23164820

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Project description:While childhood attention-deficit/hyperactivity disorder (ADHD) is more prevalent in males than females, genetic contributors to this effect have not been established. Here, we explore sex differences in the contribution of common and/or rare genetic variants to ADHD. Participants were from the Adolescent Brain and Cognitive Development study (N = 1253 youth meeting DSM-5 criteria for ADHD [mean age = 11.46 years [SD = 0.87]; 31% female] and 5577 unaffected individuals [mean age = 11.42 years [SD = 0.89]; 50% female], overall 66% White, non-Hispanic (WNH), 19% Black/African American, and 15% other races. Logistic regression tested for interactions between sex (defined genotypically) and both rare copy number variants (CNV) and polygenic (common variant) risk in association with ADHD. There was a significant interaction between sex and the presence of a CNV deletion larger than 200 kb, both in the entire cohort (β = -0.74, CI = [-1.27 to -0.20], FDR-corrected p = 0.048) and, at nominal significance levels in the WNH ancestry subcohort (β = -0.86, CI = [-1.51 to -0.20], p = 0.010). Additionally, the number of deleted genes interacted with sex in association with ADHD (whole cohort. β = -0.13, CI = [-0.23 to -0.029], FDR-corrected p = 0.048; WNH. β = -0.17, CI = [-0.29 to -0.050], FDR-corrected p = 0.044) as did the total length of CNV deletions (whole cohort. β = -0.12, CI = [-0.19 to -0.044], FDR-corrected p = 0.028; WNH. β = -0.17, CI = [-0.28 to -0.061], FDR-corrected p = 0.034). This sex effect was driven by increased odds of childhood ADHD for females but not males in the presence of CNV deletions. No similar sex effect was found for CNV duplications or polygenic risk scores. The association between CNV deletions and ADHD was partially mediated by measures of cognitive flexibility. In summary, CNV deletions were associated with increased odds for childhood ADHD in females, but not males.

Dataset Information

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

Publications

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

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