Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment.
Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment.
复制标题
通过利用多基因与教育程度的重叠揭示了与注意力缺陷/多动症相关的新基因座。
DOI：
10.1016/j.jaac.2017.11.013
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发表时间：
2018
影响因子：
13.3
通讯作者：
Johan
中科院分区：
文献类型：
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作者：
Shadrin,AlexeyA;Smeland,OlavB;Zayats,Tetyana;Schork,AndrewJ;Frei,Oleksandr;Bettella,Francesco;Witoelar,Aree;Li,Wen;Eriksen,JonA;Krull,Florian;Djurovic,Srdjan;Faraone,StephenV;Reichborn-Kjennerud,Ted;Thompson,WesleyK;Johan
目的注意缺陷多动障碍(ADHD)是一种常见的高度遗传性精神疾病。通过利用已报道的ADHD与教育程度(EA)之间的关系，我们的目标是改进ADHD相关遗传变异的发现，并调查这些表型之间的遗传重叠。方法应用条件/连接假发现率(condFDR/conjFDR)方法对ADHD(2,064个Trio，896例，2,455例对照)和EA(n=328,917例)的全基因组关联研究数据进行分析，以确定ADHD和EA的相关基因座和重叠基因座。在一项独立的基于人群的ADHD症状研究(n=17,666)中，对已识别的单核苷酸多态(SNPs)进行了相关性测试。用LD分数回归和Pearson相关分析估计ADHD与EA的遗传相关性。结果在CondFDR<；0.01和ConjFDR<；0.05水平上，我们识别了5个与ADHD相关的基因座，其中3个在ADHD和EA之间共享。所有这些基因座都没有在初级ADHD GWAS中被发现，这表明condFDR/conjFDR分析提供了更多的动力。已鉴定的5个区域中有4个位于蛋白质编码基因(KDM4A、MEF2C、PINK1、Runx1t1)的内含子内，其余1个是位于2号染色体2p24上的基因间SNP。在ADHD症状的独立研究中，5个已识别的基因座中有4个显示出一致的效应方向。显著的遗传相关性(rg=−0.403，p=7.9×10−8)和与这两个性状相关的10倍的SNPs相互丰富支持了ADHD和EA之间的多基因重叠。结论我们发现了5个与ADHD相关的新基因座，为ADHD和EA共同的遗传基础提供了证据。这些发现有助于理解ADHD的遗传风险架构及其与EA的关系。
Objective Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes. Method A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n= 328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n= 17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation. Results At levels of condFDR< 0.01 and conjFDR< 0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1), whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (r g=− 0.403, p= 7.90× 10− 8) and> 10-fold mutual enrichment of SNPs associated with both traits. Conclusion We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.