Deng Ming-Gang, Zhou Xiuxiu, Li Xiaoyan, Liu Jiewei
Wuhan Mental Health Center, Wuhan, Hubei, China; Wuhan Hospital for Psychotherapy, Wuhan, Hubei, China.
Anhui University, Hefei, Anhui, China.
J Am Acad Child Adolesc Psychiatry. 2024 Nov 5. doi: 10.1016/j.jaac.2024.10.013.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with high heritability. A total of 27 genome-wide significant loci for ADHD were previously identified through genome-wide association studies (GWASs), but the identification of risk genes that confer susceptibility to ADHD has remained largely unexplored.
As ADHD is a neurodevelopmental disorder, we integrated human brain prenatal gene and transcript expression weight data (n = 120) and ADHD GWAS summary statistics (n = 225,534; 38,691 cases and 186,843 controls) to perform a transcriptome-wide association study (TWAS) by FUSION (an analytic suite).
Our analysis identified 10 genes, including LSM6, HYAL3, METTL15, RPS26, LRRC37A15P, RP11-142I20.1, ABCB9, AP006621.5, AC000068.5, and PDXDC1, that are significantly associated with ADHD, along with 8 transcripts of 7 genes. We also conducted TWAS analysis using CommonMind Consortium (CMC) adult brain gene and gene-splicing expression weights (n = 452), which highlighted several risk genes that showed associations with ADHD in both prenatal and postnatal stages, such as LSM6 and HYAL3.
Overall, our TWAS of ADHD, by integrating human prenatal brain transcriptome and ADHD GWAS results, uncovered the cis-effects of gene/transcript regulation that are predicted to be associated with ADHD. By combining colocalization and FOCUS fine-mapping analysis, we further unraveled potential causal candidate risk genes. The risk genes/transcripts that we identified in this study can serve as a valuable resource for further investigation of the disease mechanisms underlying ADHD.
注意力缺陷多动障碍（ADHD）是一种常见的具有高遗传性的神经发育障碍。此前通过全基因组关联研究（GWAS）共鉴定出27个与ADHD相关的全基因组显著位点，但对导致ADHD易感性的风险基因的鉴定在很大程度上仍未得到充分探索。
由于ADHD是一种神经发育障碍，我们整合了人类大脑产前基因和转录本表达权重数据（n = 120）以及ADHD的GWAS汇总统计数据（n = 225,534；38,691例病例和186,843例对照），通过FUSION（一种分析套件）进行全转录组关联研究（TWAS）。
我们的分析确定了10个基因，包括LSM6、HYAL3、METTL15、RPS26、LRRC37A15P、RP11 - 142I20.1、ABCB9、AP006621.5、AC000068.5和PDXDC1，它们与ADHD显著相关，还有7个基因的8个转录本。我们还使用CommonMind联盟（CMC）的成人大脑基因和基因剪接表达权重（n = 452）进行了TWAS分析，这突出了几个在产前和产后阶段均与ADHD相关的风险基因，如LSM6和HYAL3。
总体而言，我们通过整合人类产前大脑转录组和ADHD的GWAS结果进行的ADHD的TWAS，揭示了预计与ADHD相关的基因/转录本调控的顺式效应。通过结合共定位和FOCUS精细定位分析，我们进一步揭示了潜在的因果候选风险基因。我们在本研究中鉴定出的风险基因/转录本可作为进一步研究ADHD潜在疾病机制的宝贵资源。
