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 ($\text{n}=\mathrm{328,917}$) 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 ($\text{n}=\mathrm{17,666}$). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation.

Results

At levels of $\text{condFDR}<0.01$ and $\text{conjFDR}<0.05,$ 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 (${\text{r}}_{\text{g}}=-0.403$, $p=7.90\times {10}^{-8}$) 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.

中文翻译：

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通过利用多基因重叠与教育程度，揭示了与注意力缺乏/多动障碍相关的新型基因座。

客观的

注意缺陷/多动障碍（ADHD）是一种常见且高度遗传的精神疾病。通过利用报告的多动症与教育程度（EA）之间的关系，我们旨在改善与多动症相关的遗传变异的发现，并研究这些表型之间的遗传重叠。

方法

将条件/联合虚假发现率（condFDR / conjFDR）方法应用于ADHD（2,064个三重奏，896例病例和2,455个对照）和EA的全基因组关联研究（GWAS）数据$\text{ñ}=\mathrm{328,917}$）以识别与ADHD相关的基因座以及ADHD和EA之间的基因座重叠。在一项独立的基于人群的ADHD症状研究中，对已鉴定出的单核苷酸多态性（SNP）进行了关联测试（$\text{ñ}=\mathrm{17,666}$）。使用LD评分回归和Pearson相关性估计ADHD和EA之间的遗传相关性。

结果

在水平 $\text{联邦快递}<0.01$ 和 $\text{联邦快递}<0.05，$我们确定了5个与ADHD相关的基因座，其中3个在ADHD和EA之间共享。在主要的ADHD GWAS中没有发现这些基因座，这表明condFDR / conjFDR分析提供的功能增强。5个已鉴定区域中有4个的前导SNP在蛋白质编码基因（KDM4A，MEF2C，PINK1，RUNX1T1）的内含子中，而其余的是2号染色体上2p24的基因间SNP。在5个已鉴定基因座中，有4个显示了ADHD症状独立研究中一致的效应方向。多动症和EA之间的多基因重叠由显着的遗传相关性支持（${\text{[R}}_{\text{G}}=-0.403$， $p=7.90\times {10}^{-8}$）和与这两个性状相关的SNP的> 10倍相互富集。

结论

我们确定了5个与ADHD相关的新基因座，并为ADHD和EA之间的遗传遗传基础提供了证据。这些发现可以帮助理解ADHD的遗传风险结构及其与EA的关系。