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

This study utilizing UK Biobank and FinnGen data reveals that while only postoperative atrial fibrillation yielded genome-wide significant risk loci, postoperative complications generally share a strong genetic architecture with their non-postoperative equivalents, suggesting that preoperative genetic risk scores could help stratify patients for potential surgical complications.

The Gist

Imagine your body is a high-performance race car. When you undergo major surgery, it's like putting that car through an extreme stress test: the engine is revved, the suspension is jolted, and the whole system is pushed to its limits. Sometimes, despite the best mechanics (surgeons and anesthesiologists), the car develops a problem right after the test, like a spark plug misfiring or a filter clogging. These are postoperative complications.

For a long time, doctors thought these problems were just bad luck or caused entirely by the surgery itself. But this new study asks a different question: "Is the car's blueprint (its DNA) secretly loaded with weak spots that make it more likely to break down under stress?"

Here is the breakdown of what the researchers found, using simple analogies:

1. The Big Hunt (The Study)

The researchers acted like detectives with a massive database (the UK Biobank) containing the genetic blueprints and medical records of over 140,000 people who had major surgery. They looked for five specific "breakdowns" that often happen after surgery:

• Atrial Fibrillation (AF): An irregular heartbeat (like a drumming rhythm getting out of sync).
• Acute Kidney Injury (AKI): The kidneys suddenly stop filtering well (like a clogged water filter).
• Heart Attack (MI): A blockage in the heart's fuel lines.
• Stroke: A blockage or bleed in the brain's wiring.
• Surgical Site Infection (SSI): A wound getting infected (like a rust spot forming on a new repair).

2. The Big Discovery: The Heart Rhythm "Glitch"

The most exciting finding was about Atrial Fibrillation (AF).

• The Finding: The researchers found three specific "glitches" in the genetic blueprint that made people much more likely to develop an irregular heartbeat after surgery.
• The Metaphor: Imagine your heart is a conductor leading an orchestra. In most people, the conductor is steady. But in people with these specific genetic glitches, the conductor has a slight tremor. When the surgery (the loud noise of the orchestra) happens, that tremor turns into a chaotic rhythm.
• The "New" Clue: They found one of these glitches on Chromosome 16. This is like finding a new, previously unknown weak spot in the car's chassis that no one knew about before. It seems to be a "hypothesis-generating" clue—meaning, "Hey, look here! We need to investigate this further."

3. The "Two-Part" Story: Surgery vs. Underlying Health

The study also looked at whether the "surgery version" of these diseases is genetically different from the "everyday version."

• The Analogy: Think of Atrial Fibrillation like a house with a weak roof.
  • Non-postoperative AF: The roof leaks when it rains heavily (a storm).
  • Postoperative AF: The roof leaks when you just walk on it (the stress of surgery).
• The Result: The study found that the genetic blueprint is almost the same for both. If your house has a weak roof, it will leak in a storm and it will leak if you walk on it. This means that if a patient has a genetic tendency for heart rhythm issues in daily life, they are also at high risk for it after surgery. The surgery didn't create a new problem; it just exposed the old weakness.

4. The Other Complications: A Different Story

For the other four complications (Kidney injury, Heart attack, Stroke, Infection), the story was different.

• The Finding: The researchers couldn't find any specific "glitches" in the DNA that predicted these problems after surgery.
• The Metaphor: This suggests that for these issues, the "breakdown" is less about the car's blueprint and more about how hard the stress test was or how the mechanics handled it. Maybe the kidney injury was caused by how much fluid was lost during surgery, or the infection was due to the specific bacteria in the operating room, rather than a flaw in the patient's DNA.
• However: Even without specific "surgery genes," the study found that if you have a high genetic risk for chronic kidney disease or heart disease in your daily life, you are still more likely to have a heart attack or kidney issue after surgery. It's like saying, "If your engine is already worn out, pushing it hard will break it faster."

5. What Does This Mean for the Future? (The "Crystal Ball")

The researchers suggest using Polygenic Risk Scores (PRS).

• The Metaphor: Think of a PRS as a "Risk Weather Forecast" for your DNA. Instead of just looking at your age or weight, doctors could look at your genetic forecast.
• The Application: If the forecast says, "High risk of heart rhythm glitches," the medical team could prepare a "storm kit" before the surgery even starts. They might give preventative medication or monitor the heart more closely.
• The Bigger Picture: Sometimes, a patient might have their first "storm" (a heart attack or stroke) only after surgery. This study suggests that for some people, that surgery was just the trigger that revealed a hidden, underlying genetic vulnerability they didn't know they had.

Summary

• The Good News: We found specific genetic "weak spots" that predict who will get an irregular heartbeat after surgery.
• The Connection: The genes that cause heart rhythm problems in daily life are the same ones that cause them after surgery.
• The Takeaway: Surgery is a stress test. If your genetic blueprint has weak spots, the stress test will expose them. By knowing a patient's genetic "weather forecast" before they go under the knife, doctors might be able to prevent these complications before they happen.

Technical Summary

1. Problem Statement

Postoperative complications affect up to 15% of patients undergoing major surgery globally, leading to significant morbidity, mortality, and resource utilization. While these events are known to result from an interplay between surgical trauma and individual vulnerabilities, the specific genetic architecture underlying these complications remains poorly understood. Previous Genome-Wide Association Studies (GWAS) on postoperative complications (e.g., atrial fibrillation, acute kidney injury) have been limited by small sample sizes, methodological instability in case-control imbalances, and a lack of exploration into whether postoperative events share genetic etiology with their non-postoperative (chronic/undifferentiated) counterparts. Furthermore, it is unknown if a common genetic mechanism exists across different types of postoperative complications (e.g., does the genetic risk for postoperative stroke overlap with postoperative kidney injury?).

2. Methodology

The study employed a multi-stage genomic approach using large-scale biobank data:

• Study Populations:
  • Primary Cohort: UK Biobank (>140,000 participants of European ancestry who underwent major inpatient surgery).
  • External Cohort: FinnGen (Freeze 9) used for genetic correlation with non-postoperative phenotypes.
• Phenotype Definition:
  • Outcomes: First diagnosis within 30 days post-surgery for five complications: Atrial Fibrillation (AF), Acute Kidney Injury (AKI), Myocardial Infarction (MI), Stroke, and Surgical Site Infection (SSI).
  • Controls: Patients undergoing qualifying surgery without the specific outcome within 30 days.
  • Exclusions: Prior history of the outcome, day-case surgeries, and specific procedures (e.g., cardiothoracic surgery excluded for MI analysis) to prevent reverse causality.
• Genetic Analysis:
  • GWAS: Performed using REGENIE (v3.2.2) to handle case-control imbalance. Adjusted for sex, genotyping chip, and 10 principal components. Genome-wide significance set at $p < 5 \times 10^{-8}$.
  • Functional Mapping: Used FUMA for SNP annotation and MAGMA for gene-based analysis.
  • Genetic Correlation: Assessed global correlation using LD Score Regression and local correlation using LAVA between postoperative outcomes and non-postoperative equivalents (from FinnGen).
  • Polygenic Risk Scores (PRS): Constructed ensemble PRS for non-postoperative AF, MI, Stroke, and Chronic Kidney Disease (CKD) using the Polygenic Score Catalog. These scores were tested against postoperative outcomes in the UK Biobank using logistic regression.
• Sensitivity Analyses: Included washout periods (180 days), adjustment for surgical specialty, and stratification by cardiac vs. non-cardiac surgery.

3. Key Contributions

• Largest Postoperative GWAS to Date: Conducted the most powered GWAS for postoperative complications, specifically identifying significant loci for postoperative AF where previous smaller studies failed.
• Methodological Rigor: Addressed case-control imbalance issues common in surgical cohorts by utilizing REGENIE and strict phenotype definitions.
• Cross-Phenotype Genetic Architecture: Systematically tested the hypothesis of a "shared genetic architecture" across different postoperative complications and between postoperative vs. non-postoperative forms of the same disease.
• Clinical Translation: Demonstrated the utility of existing non-postoperative PRS in predicting postoperative risk, suggesting a pathway for preoperative risk stratification.

4. Key Results

A. Genome-Wide Association Study (GWAS)

• Postoperative Atrial Fibrillation (AF): Identified three genome-wide significant loci ($p < 5 \times 10^{-8}$) across 140,563 participants:
  1. Chromosome 1: Near KCNN3 (Lead SNP: rs36088503).
  2. Chromosome 4: Near PITX2 (Lead SNP: 4:111697815_TG_T).
  3. Chromosome 16: Near TRAF7:CASKIN1 (Lead SNP: rs145672192). This is a putative novel locus for postoperative AF.
  • Note: The effect of the Chr 16 locus was robust in non-cardiac surgery but attenuated in cardiac surgery, suggesting distinct pathophysiological mechanisms.
• Other Complications: No genome-wide significant loci were found for AKI, MI, Stroke, or SSI. Exploratory thresholds ($p < 1 \times 10^{-6}$) yielded some variants, but they lacked genome-wide significance.

B. Genetic Correlation

• Inter-complication: No significant global genetic correlation was found between different postoperative complications (e.g., no overlap between postoperative AF and postoperative AKI), suggesting distinct genetic etiologies for different complication types.
• Postoperative vs. Non-Postoperative:
  • AF: Strong global genetic correlation ($r_g = 0.69, p = 0.001$) between postoperative AF and non-postoperative AF. Local correlation confirmed in regions near KCNN3 and PITX2.
  • AKI/CKD: Suggestive evidence of correlation ($r_g = 0.42, p = 0.05$) between postoperative AKI and non-postoperative CKD.
  • MI/Stroke: Insufficient SNP-based heritability prevented robust correlation analysis, though PRS results were positive.

C. Polygenic Risk Score (PRS) Analysis

• Increasing PRS quintiles for non-postoperative AF, MI, Stroke, and CKD were significantly associated with increased odds of the corresponding postoperative complication.
• AF: The association was strongest (AUC 0.83). Individuals in the highest PRS quintile had significantly higher odds of postoperative AF.
• Stratification: The PRS effect for AF was stronger in non-cardiothoracic surgery (OR 6.5 for Q5) compared to cardiothoracic surgery (OR 2.6 for Q5), reinforcing that genetic predisposition plays a larger role when direct surgical trauma (e.g., atrial manipulation) is less dominant.

5. Significance and Implications

• Genetic Vulnerability: The study confirms that postoperative AF shares a substantial genetic basis with non-postoperative AF, implicating specific genes (KCNN3, PITX2, TRAF7:CASKIN1) in the postoperative inflammatory response or arrhythmogenicity.
• "Two-Hit" Paradigm: The findings support a model where surgery acts as an inflammatory "second hit" that precipitates acute complications in individuals with underlying genetic susceptibility to chronic diseases (e.g., a patient with high genetic risk for CKD is more likely to develop AKI after surgery).
• Clinical Application:
  • Risk Stratification: Existing PRS for non-postoperative conditions could be integrated into preoperative assessments to identify high-risk patients, particularly for AF.
  • Targeted Care: High-risk patients identified via genetics could receive enhanced preventive care packages (e.g., aggressive rate control, monitoring).
  • Diagnostic Insight: An acute postoperative event may serve as the initial presentation of undiagnosed chronic pathology, warranting long-term follow-up.
• Limitations: The study is limited by the lack of external replication for the novel Chr 16 locus (FinnGen lacks postoperative phenotypes) and potential misclassification of outcomes due to reliance on coding data.

In conclusion, this research establishes a genetic foundation for postoperative AF, distinguishes it from other complications, and validates the use of polygenic risk scores to predict perioperative vulnerability, paving the way for precision medicine in surgical care.