Genetic architecture and shared mechanisms of common ′neglected′ diseases

Many diseases with significant health burden and healthcare costs have been neglected in biomedical research, partly due to a lack of data. Here, we systematically harmonized >12 million primary care and hospitalisation health records from ~440,000 UK Biobank participants into 1445 collated disease terms for genetic analyses. This included ~200 diseases with >10,000 cases that are predominantly managed in primary care, like skin and non-serious infectious diseases. We quantify the heritability for these common diseases, identify novel loci with extreme effect sizes, and highlight novel roles of poorly characterised genes, e.g. PNLIPRP3 as a sebaceous gland cell-specific gene for rosacea. We characterise the substantial regional pleiotropy with more than 300 independent genomic regions associated with multiple, often seemingly unrelated diseases and use these insights to generate a pan-genome disease network of shared disease loci to prioritise potential pathways contributing to multiple diseases and onset of multimorbidity. We demonstrate the value of primary care data to improve and guide genetic approaches for drug selection, repurposing, and adverse event prediction, e.g., IGFR1 as a putative multi-disease target for, among others, gout and atrial fibrillation, through network augmentation and integration of molecular quantitative trait loci. We make all results publicly available via an interactive webserver (https://www.omicscience.org/apps/phecodes). Our results provide new insights for diseases across diverse clinical specialties and provide a resource for drug discovery and mechanistic understanding. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement M.K. is supported by Gates Cambridge Trust. J.C.-Z. is supported by a 4-year Wellcome Trust PhD Studentship and the Cambridge Trust. ### 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 UKB was approved by the National Research Ethics Service Committee Northwest Multi-Centre Haydock and all study procedures were performed in accordance with the World Medical Association Declaration of Helsinki ethical principles for medical research. 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 All individual level data is publicly available to bona fide researchers from the UK Biobank (https://www.ukbiobank.ac.uk/). GWAS summary statistics are available from the interactive webserver upon publication (https://omicscience.org/apps/phecodes/).