Similar and different: systematic investigation of proteogenomic variation between sexes and its relevance for human diseases

To better understand sex differences in human health and disease, we conducted a systematic, large-scale investigation of sex differences in the genetic regulation of the plasma proteome (>5,000 targets), including their disease relevance. Plasma levels of two-thirds of protein targets differed significantly by sex. In contrast, genetic effects on protein targets were remarkably similar, with very few protein quantitative loci (pQTLs, n=74) showing significant sex-differential effects (for 3.9% and 0.3% of protein targets from antibody- and aptamer-based platforms, respectively). Most of these 74 pQTLs represented directionally concordant effects significant in both sexes, with only 21 pQTLs showing evidence of sexual dimorphism, i.e. effects restricted to one sex (n=20) or with opposite directions between sexes (n=1 for CDH15). None of the sex-differential pQTLs translated into sex-differential disease risk. Our results demonstrate strong similarity in the genetic regulation of the plasma proteome between sexes with important implications for genetically guided drug target discovery and validation. ### Competing Interest Statement E.W. is now an employee of AstraZeneca. ### Funding Statement We are grateful to all Fenland volunteers and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. SomaLogic proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and SomaLogic. The Fenland Study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC\_UU\_12015/1). We further acknowledge support for genomics from the Medical Research Council (MC\_PC\_13046). This work is supported by the Medical Research Council (MC\_UU\_00006/1 - Etiology and Mechanisms) (C.L., E.W., M.P., N.K., and N.J.W.). M.K. is supported by Gates Cambridge Trust. H.H. is supported by Health Data Research UK and the NIHR University College London Hospitals Biomedical Research Centre. S.D. is supported by a) the BHF Data Science Centre led by HDR UK (grant SP/19/3/34678), b) BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement 116074, c) the NIHR Biomedical Research Centre at University College London Hospital NHS Trust (UCLH BRC), d) a BHF Accelerator Award (AA/18/6/24223), e) the CVD-COVID-UK/COVID-IMPACT consortium and f) the Multimorbidity Mechanism and Therapeutic Research Collaborative (MMTRC, grant number MR/V033867/1). J.C.Z. was 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: Fenland study was approved by the Cambridge Local Research Ethics Committee (NRES Committee - East of England, Cambridge Central, ref. 04/Q0108/19) and all participants provided written informed consent. Ethics approval for the UK Biobank study was obtained from the North West Centre for Research Ethics Committee (11/NW/0382). 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 Data from the Fenland cohort can be requested by bona fide researchers for specified scientific purposes via the study website (www.mrc-epid.cam.ac.uk/research/studies/fenland/information-for-researchers/). Sex-stratified summary statistics will be made available upon publication. Access to the UK Biobank genomic, proteomic and phenotype data is open to all approved health researchers (http://www.ukbiobank.ac.uk/). This research has been conducted using the UK Biobank resource under the application 44448.