Jarick I, Volckmar A-L, Pütter C, Pechlivanis S, Nguyen T T, Dauvermann M R, Beck S, Albayrak Ö, Scherag S, Gilsbach S, Cichon S, Hoffmann P, Degenhardt F, Nöthen M M, Schreiber S, Wichmann H-E, Jöckel K-H, Heinrich J, Tiesler C M T, Faraone S V, Walitza S, Sinzig J, Freitag C, Meyer J, Herpertz-Dahlmann B, Lehmkuhl G, Renner T J, Warnke A, Romanos M, Lesch K-P, Reif A, Schimmelmann B G, Hebebrand J, Scherag A, Hinney A
Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany.
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
Mol Psychiatry. 2014 Jan;19(1):115-21. doi: 10.1038/mp.2012.161. Epub 2012 Nov 20.
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.
注意力缺陷多动障碍（ADHD）是一种常见的、高度可遗传的神经发育障碍。全基因组关联研究尚未确定其相关基因位点。罕见的拷贝数变异（CNV），如染色体缺失或重复，已被认为与ADHD及其他神经发育障碍有关。为了确定增加ADHD风险的罕见（频率≤1%）CNV，我们基于489名年轻ADHD患者和1285名成年人群对照进行了全基因组CNV分析，并确定了一个显著相关的CNV区域。在对大型（>500 kb）罕见CNV的总体负担测试中，我们观察到ADHD病例组中携带至少一个此类CNV的受试者富集率为1.126倍，但差异无统计学意义（P = 0.271）。采用位点特异性关联测试来评估病例组与对照组相比是否存在更多罕见CNV。在ADHD组中显著富集的检测到的CNV通过定量（q）PCR进行了验证。研究结果在386名年轻ADHD患者和781名年轻人群健康对照的独立样本中得到了重复验证。我们在帕金森蛋白2基因（PARK2）内发现了罕见的CNV，ADHD患者中的患病率显著高于对照组（经全基因组测试的经验性校正后，P = 2.8 × 10^(-4)）。总体而言，PARK2基因座（染色体6：162 659 756 - 162 767 019）在ADHD患者中有3个缺失和9个重复，在对照组中有2个缺失和2个重复。通过qPCR分析，我们验证了ADHD患者12个CNV中的11个（经全基因组测试的经验性校正后，P = 1.2 × 10^(-3)）。在重复样本中，在另外4名ADHD患者和1名对照中发现了PARK2基因座的CNV（P = 4.3 × 10^(-2)）。我们的结果表明，PARK2基因座的拷贝数变异有助于ADHD的遗传易感性。已知PARK2中的突变和CNV与帕金森病有关。
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