Dissecting the contribution of common variants to risk of rare neurodevelopmental conditions

Although rare neurodevelopmental conditions have a large Mendelian component, common genetic variants also contribute to risk. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents, its interplay with rare variants, and whether parents' polygenic background contributes to their children's risk beyond the direct effect of variants transmitted to the child (i.e. via indirect genetic effects potentially mediated through the prenatal environment or 'genetic nurture'). 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 ~10% of variance in overall risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model, while both genetically undiagnosed patients and diagnosed patients with affected parents had significantly more risk than controls. In a trio-based model, using a polygenic score for neurodevelopmental conditions, the transmitted but not the non-transmitted parental alleles were associated with risk, indicating a direct genetic effect. In contrast, we observed no direct genetic effect of polygenic scores for educational attainment and cognitive performance, but saw a significant correlation between the child's risk and non-transmitted alleles in the parents, potentially due to indirect genetic effects and/or parental assortment for these traits. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. Our findings thus suggest 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. ### Competing Interest Statement Matthew Hurles is non-executive director and holds stock in Congenica Inc., and is also a consultant for AstraZeneca. ### Funding Statement DDD: The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003). The full acknowledgements can be found at www.ddduk.org/access.html. This study makes use of DECIPHER, which is funded by the Wellcome Trust. GEL: This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. UK Household Longitudinal Study: We used data from 'Understanding Society: The UK Household Longitudinal Study', which is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council (grant number ES/M008592/1). ALSPAC: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This research was funded in part by Wellcome (grant no. 220540/Z/20/A, "Wellcome Sanger Institute Quinquennial Review 2021-2026"). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Cambridge South Research Ethics Committee gave ethical approval for this work The Republic of Ireland Research Ethics Committee gave ethical approval for this work The East of England-Cambridge Central Research Ethics Committee gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The raw and post-quality control genotype array data and exome sequence data from DDD are available through European Genome-phenome Archive, under EGAS00001000775. Whole-genome sequence data and phenotypic data from the 100,000 Genomes project can be accessed by application to Genomics England (https://www.genomicsengland.co.uk/research/academic/join-gecip). GWAS summary statistics of neurodevelopmental conditions generated in this study are available in Supplementary Data. Researchers can apply to access genotype array data from ALSPAC (https://www.bristol.ac.uk/alspac/researchers/access/) and MCS (https://cls.ucl.ac.uk/data-access-training/data-access/). Publicly available GWAS summary statistics can be accessed at various resources: http://www.thessgac.org/data, https://pgc.unc.edu/for-researchers/download-results/, and https://egg-consortium.org/Gestational-duration-2023.html.