One gene locus flags atrial fibrillation risk after major surgery, UK Biobank study finds

Up to 15 percent of patients worldwide experience serious complications after major surgery, and a new genome-wide study asks whether the risk of those complications is written in DNA. Using health records and genetic data from more than 140,000 UK Biobank participants who underwent major surgery, researchers carried out case-control genome-wide association studies of five common postoperative complications: acute kidney injury, atrial fibrillation, myocardial infarction, stroke and surgical site infection. The work, published in BMC Medical Genomics, also tested whether the genetic basis of complications after surgery overlaps with the genetic basis of the same diseases in people who have not had surgery.

The search for genetic risk factors delivered one clear hit. Among 8,196 postoperative complications recorded in the 140,561 eligible participants, the team found a single genome-wide significant risk locus for postoperative atrial fibrillation, located on chromosome 4 in the PITX2 gene region. No genome-wide significant loci emerged for acute kidney injury, myocardial infarction, stroke or surgical site infection.

Genome-wide association studies scan hundreds of thousands of genetic variants across the genome, comparing how often each variant appears in people who developed a condition versus those who did not. Because a single variant’s effect is usually tiny, statistical thresholds for genome-wide significance are strict, which protects against false positives but also means that studies of relatively uncommon outcomes, such as specific surgical complications, often lack the power to detect more than the strongest signals. That constraint likely explains why only one locus cleared the bar across the five complications examined.

The researchers then asked a subtler question: do postoperative complications share their genetic architecture with the non-postoperative versions of the same diseases? To probe this, they assessed genetic correlation between the UK Biobank postoperative outcomes and their undifferentiated, non-postoperative equivalents drawn from the FinnGen cohort. For atrial fibrillation, the analysis found local genetic correlation in the KCNN3 region, with a correlation estimate of rho equal to 0.47 and a p value of 1.9 times ten to the minus seven. Local genetic correlation examines whether the same stretch of the genome influences both traits, and a positive value here indicates that the KCNN3 region contributes to atrial fibrillation risk in similar ways whether or not surgery is involved.

Polygenic risk scores provided a second line of evidence. A polygenic risk score condenses the combined effect of many genetic variants into a single number that estimates a person’s inherited predisposition to a trait. The team tested whether scores built for non-postoperative phenotypes predicted the corresponding complications after surgery. Increasing quintiles of the polygenic risk score for non-postoperative atrial fibrillation were associated with increasing odds of developing postoperative atrial fibrillation, and the same pattern held for non-postoperative myocardial infarction, stroke and chronic kidney disease in relation to their postoperative counterparts.

That gradient matters because it suggests a dose-response-like relationship: the higher a patient’s inherited risk for a chronic disease, the greater the odds of experiencing the acute version of that disease after major surgery. For chronic kidney disease, the relevant postoperative complication is acute kidney injury, one of the most closely watched outcomes after major operations. The consistency across four separate phenotype pairs strengthens the interpretation that these postoperative events are not entirely discrete accidents of surgery but partly reflect an underlying chronic disease vulnerability that surgery exposes.

The study also looked across complications rather than within them, assessing whether the five postoperative outcomes share genetic basis with one another. It found no shared genetic basis across different complications. In other words, the genetic factors that raise the odds of postoperative atrial fibrillation are not the same as those that raise the odds of postoperative acute kidney injury or infection, at least as far as this study could detect.

The authors draw a practical implication from the pattern. Because polygenic risk scores for several non-postoperative phenotypes were associated with their postoperative equivalents, they suggest that postoperative complications may reflect underlying chronic disease vulnerability, with potential implications for postoperative follow-up. The study itself did not test such a monitoring strategy, so any clinical application remains a hypothesis for future work rather than a demonstrated benefit.

The findings come with the limitations inherent to the design. The analysis relied on UK Biobank participants, and the number of postoperative events, though substantial at 8,196, limited statistical power for several of the five complications. The absence of genome-wide significant loci for acute kidney injury, myocardial infarction, stroke and surgical site infection does not prove that genetics plays no role in those outcomes; it means no single variant reached the strict significance threshold in this sample. Genetic correlation and polygenic score analyses add evidence of shared biology, but they describe population-level associations rather than predictions for any individual patient.

Even so, the study marks a step in an emerging research direction: treating complications after surgery as genetically linked to chronic disease rather than as isolated surgical mishaps. The PITX2 locus for postoperative atrial fibrillation, the KCNN3 shared signal and the polygenic score associations together sketch a picture in which the operating table reveals risks that were present all along. Larger cohorts and more postoperative events will be needed to map the genetics of the other four complications with the same confidence, and to determine whether inherited risk can be turned into better preoperative assessment and follow-up for the millions of people who undergo major surgery each year.

Subject of Research: Genetic risk factors for postoperative complications after major surgery and their shared genetic basis with non-postoperative diseases

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

Article References: Armstrong, R. A., Yousefi, P., Gibbison, B., Khandaker, G. M., & Gaunt, T. R. (2026). Genetic risk factors for postoperative complications after major surgery and shared genetic aetiology with non-postoperative phenotypes. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02487-3

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02487-3

Keywords: genome-wide association study, UK Biobank, postoperative complications, atrial fibrillation, PITX2, polygenic risk score, acute kidney injury, genetic correlation, FinnGen, major surgery, chronic kidney disease, BMC Medical Genomics