Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Biol Psychiatry. 2020 Sep 15;88(6):470-479. doi: 10.1016/j.biopsych.2020.05.002. Epub 2020 May 16.
Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels.
We applied summary-data-based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data-based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels.
We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before.
Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies.
最近的全基因组关联研究（GWAS）确定了与注意力缺陷/多动障碍（ADHD）和自闭症谱系障碍（ASD）相关的第一个遗传位点。下一步是利用这些结果来增加我们对所涉及的生物学机制的理解。大多数已确定的变体可能会影响基因调控。本研究旨在通过整合 GWAS 结果与基因表达和 DNA 甲基化（DNAm）水平，阐明遗传信号背后的机制，并对基因进行优先级排序。
鉴于这些疾病的发病年龄较早，我们应用基于汇总数据的孟德尔随机化，将 ADHD 和 ASD 的 GWAS 数据与胎儿大脑表达和甲基化数量性状基因座（mQTL）进行整合。我们还分析了成人大脑和血液的表达和甲基化数量性状基因座数据集，因为这些数据集提供了更大的统计效力。随后，我们使用基于汇总数据的孟德尔随机化来研究相同的变异是否会同时影响 DNAm 和基因表达水平。
我们在染色体 1 和 17 上发现了多个与 ADHD 和 ASD 分别相关的胎儿大脑基因表达和 DNAm 水平，这些水平是通过共享遗传变异的多效性产生的。大脑和血液中的分析显示，在相同和其他位置还存在额外的相关基因表达和 DNAm 水平，这可能是由于统计效力的增加。以前在 ADHD 和 ASD 的 GWAS 中尚未发现一些相关基因。
我们的研究结果确定了与 ADHD 和 ASD 相关的遗传变异，这些变异可能通过基因调控发挥作用。这有助于为功能后续研究优先选择候选基因。
