Examining the role of common variants in rare neurodevelopmental conditions

• 成果类型: Article
• 署名作者: Huang, Qin Qin; Wigdor, Emilie M.; Malawsky, Daniel S.; Campbell, Patrick; Samocha, Kaitlin E.; Chundru, V. Kartik; Danecek, Petr; Lindsay, Sarah; Marchant, Thomas; Koko, Mahmoud; Amanat, Sana; Bonfanti, Davide; Sheridan, Eamonn; Radford, Elizabeth J.; Barrett, Jeffrey C.; Wright, Caroline F.; Firth, Helen V.; Warrier, Varun; Strudwick Young, Alexander; Hurles, Matthew E.; Martin, Hilary C.
• 署名单位: Wellcome Trust Sanger Institute; University of London; King's College London; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Exeter; University of Leeds; Saint James's University Hospital; Chapel Allerton Hospital; University of Cambridge; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; University of Cambridge; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4446
• DOI: 10.1038/s41586-024-08217-y
• 发表日期: 2024-12-12
• 页码: 404-411
• 关键词: missing heritability; metaanalysis; association; RISK; liability; resource; uk

摘要

Although rare neurodevelopmental conditions have a large Mendelian component(1), common genetic variants also contribute to risk(2,3). However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment(4) also play a role. Here we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained around 10% of variance in risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model(5). A polygenic score for neurodevelopmental conditions showed only a direct genetic effect. By contrast, polygenic scores for educational attainment and cognitive performance showed no direct genetic effect, but the non-transmitted alleles in the parents were correlated with the child's risk, potentially due to indirect genetic effects and/or parental assortment for these traits(4). Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. These findings indicate that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.