Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Mol Psychiatry. 2023 Aug;28(8):3493-3502. doi: 10.1038/s41380-023-02200-1. Epub 2023 Aug 3.
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. We performed a transcriptome-wide association study (TWAS) using the latest genome-wide association study (GWAS) meta-analysis, in 38,691 individuals with ADHD and 186,843 controls, and 14 gene-expression reference panels across multiple brain tissues and whole blood. Based on TWAS results, we selected subsets of genes and constructed transcriptomic risk scores (TRSs) for the disorder in peripheral blood mononuclear cells of individuals with ADHD and controls. We found evidence of association between ADHD and TRSs constructed using expression profiles from multiple brain areas, with individuals with ADHD carrying a higher burden of TRSs than controls. TRSs were uncorrelated with the polygenic risk score (PRS) for ADHD and, in combination with PRS, improved significantly the proportion of variance explained over the PRS-only model. These results support the complementary predictive potential of genetic and transcriptomic profiles in blood and underscore the potential utility of gene expression for risk prediction and deeper insight in molecular mechanisms underlying ADHD.
注意缺陷多动障碍（ADHD）是一种高度遗传性的神经发育障碍。我们使用最新的全基因组关联研究（GWAS）荟萃分析，对 38691 名 ADHD 患者和 186843 名对照者，以及来自多个大脑组织和全血的 14 个基因表达参考面板进行了全转录组关联研究（TWAS）。基于 TWAS 结果，我们选择了基因子集，并在 ADHD 患者和对照者的外周血单核细胞中构建了该疾病的转录组风险评分（TRS）。我们发现，使用来自多个大脑区域的表达谱构建的 ADHD 和 TRS 之间存在关联的证据，ADHD 患者携带的 TRS 负担高于对照组。TRS 与 ADHD 的多基因风险评分（PRS）不相关，与 PRS 结合使用时，显著提高了 PRS 模型解释方差的比例。这些结果支持血液中遗传和转录组谱的互补预测潜力，并强调了基因表达在风险预测和 ADHD 潜在分子机制方面的深入见解方面的潜在效用。
