Genetic risk factors for postoperative complications after major surgery and shared genetic aetiology with non-postoperative phenotypes

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Abstract 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 ( r g = 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 We identified multiple genomic risk loci for postoperative AF, including a putative novel locus on chromosome 16, and demonstrated shared genetic architecture with non-postoperative AF. Although no shared genetic basis was found across different complications, the association between PRS for several non-postoperative phenotypes and their postoperative equivalents suggests that postoperative complications may reflect underlying chronic disease vulnerability with potential implications for targeted risk stratification and postoperative follow-up.

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