Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants

Abstract Studying the genetics of measures of intelligence can help us understand the neurobiology of cognitive function and the aetiology of rare neurodevelopmental conditions. The largest previous genetic studies of measures of intelligence have used ∼270k individuals who completed the fluid intelligence (FI) test in UK Biobank. Here, we integrate additional FI measures in this cohort and leverage eighty-two correlated variables to impute FI values for unmeasured individuals, increasing the sample size to >450k. Through population-based and within-family genome-wide association studies and downstream analyses, we show that this imputation produces a phenotype that genetically resembles measured FI and reduces ascertainment bias within the cohort. We further show that combining measured and imputed FI scores increases the number of independent SNP associations (p<5×10-8) from 385 to 608 and increases polygenic score accuracy in external cohorts by 15% on average. Additionally, incorporating imputed FI scores increases the number of gene-level associations with rare variants from five to twenty-six (FDR<1%). These include fourteen well-established developmental disorder-associated genes, a four-fold enrichment (p=8×10-8); for several of these, our results suggest that loss-of-function variants in the gene impact neurodevelopment, in addition to the previously documented altered-function variants. We also implicate twelve genes without strong prior evidence of association developmental disorders, of which eight have not been previously linked to intelligence (ROBO2, RB1CC1, ANK3, CHD9, TLK1, PCLO, DPP8, IPO9). These twelve genes were significantly enriched for de novo loss-of-function mutations in a set of >31k patients with developmental disorders (p=6.8×10-4). We further identify three genes showing significant rare variant associations with educational attainment but not with FI, including CADPS2 in which, unusually, protein-truncating variants show a positive association. Our results demonstrate the power of phenotype imputation for genetic studies and suggest that incorporating genetic association results for cognitive phenotypes in the general population could help discover new developmental disorder genes. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was conducted using the UK Biobank Resource under application numbers 40310 and 44165. This work used the Dutch national e infrastructure with the support of the SURF Cooperative using grant no. EINF 7294. This research was funded in part by Wellcome (grant no. 220540/Z/20/A, Wellcome Sanger Institute Quinquennial Review 2021 to 2026). K.J.H.V. is supported by the Foundation Volksbond Rotterdam. A.A. is supported by the Amsterdam UMC Fellowship. For the purpose of open access, the authors have applied a CC-BY public copyright license to any author accepted manuscript version arising from this submission. 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: UK Biobank has received ethical approval from the National Health Service North West Centre for Research Ethics Committee (reference: 11/NW/0382) and gave approval for this work. Ethics committee of ALSPAC gave ethical approval for this work Ethics committee of MCS name 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 Footnotes ↵# These authors jointly supervised the work. Data availability statement UK Biobank data are available to researchers upon application (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). The imputed fluid intelligence phenotype is not publicly available due to participant privacy and UK Biobank’s data sharing policies but can be regenerated by approved researchers using the code provided on GitHub (https://github.com/dmvandenberg/UKB-FI-Imputation). Summary statistics from population and within-family based GWAS of combined FIS, measured FIS, Imputed FIS, and the meta-analysis of combined FIS and COGENT will be made available via the GWAS Catalog upon peer reviewed publication. Full results of rare variant analyses, including gene-level association statistics are available in the Supplements.