Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment,Journal of the American Academy of Child and Adolescent Psychiatry

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Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment
Journal of the American Academy of Child and Adolescent Psychiatry ( IF 9.2 ) Pub Date : 2017-11-26 , DOI: 10.1016/j.jaac.2017.11.013
Alexey A Shadrin ₁ , Olav B Smeland ₁ , Tetyana Zayats ₂ , Andrew J Schork ₃ , Oleksandr Frei ₁ , Francesco Bettella ₁ , Aree Witoelar ₁ , Wen Li ₁ , Jon A Eriksen ₁ , Florian Krull ₁ , Srdjan Djurovic ₄ , Stephen V Faraone ₅ , Ted Reichborn-Kjennerud ₆ , Wesley K Thompson ₇ , Stefan Johansson ₈ , Jan Haavik ₉ , Anders M Dale ₁₀ , Yunpeng Wang ₁₁ , Ole A Andreassen ₁

Affiliation

NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
University of California, San Diego and Institute of Biological Psychiatry, Medical Health Center, Sct. Hans Hospital and University of Copenhagen, Copenhagen, Denmark.
Oslo University Hospital, Oslo, and NORMENT, KG Jebsen Centre for Psychosis Research, University of Bergen.
KG Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, SUNY Upstate Medical University, Syracuse, New York.
Division of Mental Health, Norwegian Institute of Public Health, Oslo, and Institute of Clinical Medicine, University of Oslo.
University of California, San Diego.
K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital.
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, and University of California, San Diego.
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; University of California, San Diego, La Jolla, CA.

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 ( $r_{g} = - 0.403$ , $p = 7.90 \times 10^{- 8}$ ) 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：

通过利用多基因与教育程度的重叠揭示与注意力缺陷/多动症相关的新基因座

客观的

注意力缺陷/多动障碍（ADHD）是一种常见且高度遗传的精神疾病。通过利用已报道的 ADHD 和教育程度 (EA) 之间的关系，我们的目的是改进 ADHD 相关遗传变异的发现，并研究这些表型之间的遗传重叠。

方法

将条件/结合错误发现率 (condFDR/conjFDR) 方法应用于 ADHD（2,064 个三人组、896 个病例和 2,455 个对照）和 EA 的全基因组关联研究 (GWAS) 数据。 $n = 328,917$ ) 识别 ADHD 相关基因座以及 ADHD 和 EA 之间重叠的基因座。在一项基于人群的独立 ADHD 症状研究中，对已鉴定的单核苷酸多态性 (SNP) 进行了关联性测试（ $n = 17,666$ ）。 ADHD 和 EA 之间的遗传相关性使用 LD 评分回归和 Pearson 相关性进行估计。

结果

在水平 $条件FDR < 0.01$ 和 $联合FDR < 0.05,$ 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 ADHD GWAS 中尚未发现这些位点，这表明 condFDR/conjFDR 分析提供了增强的功效。 5 个已识别区域中的 4 个的主要 SNP 位于蛋白质编码基因的内含子中（ KDM4A 、 MEF2C、PINK1、RUNX1T1），而其余一个是 2 号染色体 2p24 处的基因间 SNP。在 ADHD 症状的独立研究中，5 个已识别位点中的 4 个显示出一致的影响方向。 ADHD 和 EA 之间的多基因重叠得到了显着遗传相关性的支持（ $r_{克} = - 0.403$ , $p = 7.90 \times 10^{- 8}$ ）并且与这两个性状相关的 SNP 相互富集 >10 倍。