Background Up to 15% of patients worldwide experience serious postoperative complications after major surgery. We explored the genetic basis of five common postoperative complications and whether they share genetic aetiology with their non-postoperative equivalents.

Methods We performed case-control genome-wide association studies (GWAS) using UK Biobank data from >140,000 participants. The primary outcomes were postoperative acute kidney injury (AKI), atrial fibrillation (AF), myocardial infarction (MI), stroke and surgical site infection (SSI). Additionally, we assessed genetic correlation between UK Biobank postoperative outcomes, as well as between these and their non-postoperative (undifferentiated) equivalents from the FinnGen cohort. Finally, we assessed the association between observed postoperative outcomes and polygenic risk scores (PRS) for their non-postoperative equivalents.

Results Among 8,472 postoperative complications in 140,563 eligible participants, three genome-wide significant risk loci for AF were identified on chromosomes 1 (KCNN3), 4 (PITX2) and 16 (TRAF7:CASKIN1). No genome-wide significant loci were found for AKI, MI, stroke or SSI. Strong genetic correlation between postoperative and non-postoperative AF was found (rg = 0.69, p = 0.001). Increasing PRS quintiles for non-postoperative AF, MI, stroke and chronic kidney disease were associated with increased odds of developing the corresponding postoperative complication.

Conclusions In addition to identifying a novel genomic risk loci associated with postoperative AF, we show that postoperative complications and their non-postoperative equivalents share genetic architecture. These findings suggest that postoperative complications may represent the acute manifestation of underlying genetic vulnerability, which has implications for preoperative risk stratification and postoperative clinical management.

TRG receives funding from GlaxoSmithKline, Biogen and Roche for unrelated research. The other authors declare that they have no conflict of interest.

RAA is funded by a Wellcome Trust GW4-CAT PhD Programme for Health Professionals PhD Fellowship [316275/Z/24/Z]. RAA, PY, GMK and TRG are supported by the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (RA, TG: MC_UU_00032/3; PY: MC_UU_00032/4; GMK: MC_UU_0032/6). GMK acknowledges additional funding from the Wellcome Trust (grant numbers: 201486/Z/16/Z and 201486/B/16/Z), the Medical Research Council (grant numbers: MR/W014416/1; MR/S037675/1; MR/Z50354X/1; and MR/Z503745/1. PY, TRG, and GMK are also supported by the UK National Institute for Health and Care Research (NIHR) Bristol Biomedical Research Centre (grant number: NIHR 203315). The views expressed are those of the authors and not necessarily those of the UK NIHR or the Department of Health and Social Care.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The primary analysis was conducted in UK Biobank. The UK Biobank study was approved by the North-West Multi-centre Research Ethics Committee and all participants provided written informed consent. This research has been conducted under UK Biobank project number 128619.

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Summary statistics will be publicly available on publication. Source data are available from UK Biobank (http://www.ukbiobank.ac.uk) and Finngen (https://r9.finngen.fi) through their access procedures.