Examining the role of common variants in rare neurodevelopmental conditions

Qin Qin Huang, Emilie M. Wigdor, Daniel S. Malawsky, Patrick Campbell, Kaitlin E. Samocha, V. Kartik Chundru, Petr Danecek, Sarah Lindsay, Thomas Marchant, Mahmoud Koko, Sana Amanat, Davide Bonfanti, Eamonn Sheridan, Elizabeth J. Radford, Jeffrey C. Barrett, Caroline F. Wright, Helen V. Firth, Varun Warrier, Alexander Strudwick Young, Matthew E. Hurles and Hilary C. Martin ()
Additional contact information
Qin Qin Huang: Wellcome Sanger Institute
Emilie M. Wigdor: Wellcome Sanger Institute
Daniel S. Malawsky: Wellcome Sanger Institute
Patrick Campbell: Wellcome Sanger Institute
Kaitlin E. Samocha: Massachusetts General Hospital
V. Kartik Chundru: Wellcome Sanger Institute
Petr Danecek: Wellcome Sanger Institute
Sarah Lindsay: Wellcome Sanger Institute
Thomas Marchant: Wellcome Sanger Institute
Mahmoud Koko: Wellcome Sanger Institute
Sana Amanat: Wellcome Sanger Institute
Davide Bonfanti: Wellcome Sanger Institute
Eamonn Sheridan: Wellcome Sanger Institute
Elizabeth J. Radford: Wellcome Sanger Institute
Jeffrey C. Barrett: Wellcome Sanger Institute
Caroline F. Wright: University of Exeter
Helen V. Firth: Wellcome Sanger Institute
Varun Warrier: University of Cambridge
Alexander Strudwick Young: University of California Los Angeles Anderson School of Management
Matthew E. Hurles: Wellcome Sanger Institute
Hilary C. Martin: Wellcome Sanger Institute

Nature, 2024, vol. 636, issue 8042, 404-411

Abstract: Abstract Although rare neurodevelopmental conditions have a large Mendelian component1, common genetic variants also contribute to risk2,3. 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 environment4 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 model5. 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 traits4. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08217-y

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