Preventing premature deaths through polygenic risk scores

#1

A groundbreaking modeling study published in Nature Communications quantifies the potential of Polygenic Risk Scores (PRS) to revolutionize preventive medicine. Researchers from Genomics plc and Stanford University analyzed data from over 330,000 UK Biobank participants to model the “Risk Advancement Period” (RAP)—the number of years earlier a genetically high-risk individual reaches the disease threshold typically used to trigger screening.

The “Big Idea” is that biological risk age is often divorced from chronological age. The study found that individuals in the top 25% of genetic risk (High Risk) reach the critical risk threshold for diseases like breast cancer, type 2 diabetes, and coronary artery disease on average 8.9 years earlier than the general population. For the “Very High Risk” group (top ~6%), this gap widens to 10.8 years. Conversely, those with low genetic risk may not reach the screening threshold until 16 years after current guidelines suggest.

By applying these genetic insights to US screening guidelines, the authors estimate that PRS-guided early intervention could prevent 23.3% of premature deaths in the high-risk group. This moves longevity medicine from “one-size-fits-all” checkups to precision scheduling, where your genome dictates your calendar.

Source:

  • Open Access Paper: Preventing premature deaths through polygenic risk scores
  • Institution: Genomics plc (UK), Stanford University (USA).
  • Journal: Nature Communications.
  • Impact Evaluation: The impact score of this journal is 15.7 (2024 JIF), evaluated against a typical high-end range of 0–60+, therefore this is a High impact journal.

The Biohacker Analysis

Study Design Specifications

  • Type: Retrospective Cohort Modeling & Simulation.
  • Subjects: 332,664 individuals from the UK Biobank (Testing Set), primarily of European ancestry.
  • Lifespan Analysis: This is a human mortality modeling study. It estimates “premature deaths prevented” rather than measuring maximum lifespan extension in a model organism.
  • Data Source: UK Biobank (genotype/phenotype), US SEER (cancer incidence), CDC (mortality), and USPSTF (screening guidelines).

Mechanistic Deep Dive: The “Risk Advancement Period” (RAP) Unlike a drug study targeting a pathway (e.g., mTOR), this research targets the statistical architecture of risk.

  • The Mechanism: The PRS aggregates thousands of small-effect Single Nucleotide Polymorphisms (SNPs) into a single score. This score acts as a “background multiplier” for disease probability.
  • The RAP Concept: If the general population reaches a 1% risk of Colon Cancer at age 45 (triggering a colonoscopy), a person with a PRS Odds Ratio (OR) of 2.0 might reach that same 1% risk at age 37.
  • Longevity Relevance: This directly informs “Healthspan Defense.” Biohackers often focus on slowing aging, but avoiding premature death from a treatable pathology (e.g., finding a polyp at 35 instead of 45) is the highest-ROI longevity intervention available.

Novelty

  • Quantification of Time: Previous studies established PRS predicts risk; this study translates that abstract risk into a concrete metric: Time. (e.g., “Your genes make your colon 8 years older than your birthday implies.”)
  • Multi-Morbidity View: It assesses 7 major killers simultaneously, finding that 25% of people are “High Risk” for at least one of these conditions, debunking the idea that high genetic risk is rare.

Critical Limitations

  • Ancestry Bias: The PRS effect sizes were derived primarily from European ancestry data (UK Biobank). The authors acknowledge that accuracy may drop for other ancestries, though sensitivity analyses suggest the conceptholds.
  • Modeling vs. Reality: The “23.3% deaths prevented” is a simulation. It assumes that screening a 35-year-old is as effective as screening a 50-year-old (same sensitivity/specificity), which may not be true (e.g., denser breast tissue in younger women reduces mammogram efficacy).
  • Overdiagnosis Risk: Earlier screening increases the detection of “indolent” tumors that might never have caused death, potentially leading to unnecessary surgeries/treatments (harm).

Claims Analysis

Claim 1: Polygenic Risk Scores (PRS) can effectively stratify the population into High, Average, and Low risk groups for 7 common diseases.

Claim 2: High-risk individuals (PRS OR > 2) reach the clinical risk threshold for screening ~9-11 years earlier than the general population.

Claim 3: Implementing PRS-guided screening could reduce premature disease-specific deaths by 23.3% in high-risk groups.

  • Verification: This is a theoretical estimate. It relies on the assumption that early detection via screening reduces mortality at the same rate as standard-age screening (e.g., mammography reduces mortality by ~12-20%). Real-world implementation trials are needed to confirm this specific % reduction.
  • Evidence Level: Level D (Mathematical Modeling based on RCT parameters).
  • Source: Preventing premature deaths through polygenic risk scores (2025) (Current Paper)

Claim 4: Current Breast Cancer screening guidelines (USPSTF) start at age 40.

Actionable Intelligence: The “Protocol of Time”

Since the “intervention” here is information, not a drug, the protocol focuses on Screening Calibration.

1. The “Dose” is Time (Calculating Your RAP)

  • Step 1: Get Sequenced. Use a high-density array or Whole Genome Sequencing (WGS) service that offers clinical-grade PRS reports (e.g., Genomics plc partners, 23andMe+ Health, Nebula, or specialized clinics).
  • Step 2: Identify Your “High Risk” Buckets. Look for any disease where your percentile is >90th (High Risk) or >97th (Very High Risk).
  • Step 3: Apply the “Decade Shift” Rule.
    • High Risk (Top 20-25%): Assume your biological risk age is +5 to +9 years older than your chronological age.
    • Very High Risk (Top 5%): Assume your biological risk age is +10 to +12 years older.
  • Step 4: Shift Screening.
    • Colorectal: If high risk, consider initiating colonoscopy at 35-40 (Standard is 45).
    • Breast (Females): If high risk, consider annual MRI/Mammogram starting at 30-34 (Standard is 40).
    • Prostate (Males): If high risk, baseline PSA at 40 (Standard is 55 or “shared decision”).

2. Biomarker Verification Panel (Safety Monitoring) If your PRS indicates high susceptibility, use specific biomarkers to monitor phenotypic expression.

  • Coronary Artery Disease (CAD):
    • PRS Risk: High.
    • Action: Aggressive LDL/ApoB targets (<60 mg/dL). Monitor Lp(a) once (often elevated in high PRS cases).
  • Type 2 Diabetes (T2D):
    • PRS Risk: High.
    • Action: Continuous Glucose Monitor (CGM) usage and annual Fasting Insulin + HbA1c. Early Metformin consideration.
  • Prostate Cancer:
    • PRS Risk: High.
    • Action: PSA velocity monitoring starting age 40.

3. Feasibility & ROI

  • Cost: Consumer Whole Genome Sequencing /PRS costs $200–$500 (one-time).
  • Benefit: Potential to detect lethal cancers (Stage I vs Stage IV) or preventing heart attacks.
  • ROI: Extremely High. A $300 test offering a 10-year head start on cancer detection is arguably the most cost-effective biohack available.

4. Safety Check: The “Overdiagnosis” Trap

  • Contraindication: Do not use PRS to skip screening without medical advice. While the paper suggests low-risk people could delay screening, current guidelines do not support delaying proven screens (like Colonoscopy) based on PRS alone due to false negatives.
  • Anxiety Risk: High PRS does not mean you will get the disease. It means your threshold is lower.

The Strategic FAQ

Q1: Does this paper suggest I can stop screening if my PRS is low?

  • Answer: The modeling suggests low-risk individuals could theoretically delay screening by ~10 years, but don’t do it yet. The safety of “de-escalation” hasn’t been proven in trials. You might have a low PRS but a rare mutation (like Lynch syndrome) or environmental exposure (smoking) that the PRS misses.

Q2: How does this interact with Rapamycin or other longevity drugs?

  • Answer: It helps you stratify risk. If you are high-risk for Type 2 Diabetes (T2D), And you are taking a high dose of rapamycin (e.g. 10mg to 15mg per week) Rapamycin’s potential side effect of insulin resistance/hyperglycemia might be more of a risk for you. You may need stricter glucose monitoring or concurrent Metformin/Acarbose.

Q3: Can I get this exact “Risk Advancement Period” report today?

  • Answer: Not exactly as presented in the paper. While services like 23andMe or Nebula provide “risk percentiles,” they rarely calculate the specific “RAP” (e.g., “Screen at age 34”). You must manually infer this: if you are in the 95th percentile, assume a ~10-year acceleration.

Q4: Is this just for White/European people?

  • Answer: Mostly, yes. The UK Biobank is predominantly European. The paper explicitly notes that while the concept works for all ancestries, the accuracy of current scores drops for African, Asian, and Hispanic populations.

Q5: Does a High PRS mean I have a disease?

  • Answer: No. It is probabilistic, not deterministic. It means your “bucket” fills up faster. You can empty the bucket with lifestyle interventions (exercise, diet, sleep) which can offset genetic risk by ~30-50%.

Q6: Why isn’t my doctor using this yet?

  • Answer: Clinical inertia and lack of guidelines. The USPSTF does not yet recommend PRS. Most doctors don’t know how to interpret a “polygenic hazard ratio.” You will likely need to advocate for yourself or see a specialized longevity physician.

Q7: Does insurance cover this?

  • Answer: Generally, no. It is considered “investigational” for screening purposes. However, in the US, the GINA act protects you from health insurance discrimination based on genetic results (but not life or disability insurance).

Q8: How does PRS differ from testing for BRCA1/2?

  • Answer: BRCA is a monogenic (single gene) mutation with massive effect (e.g., 60-80% risk). PRS is polygenic(thousands of genes) with moderate effect (e.g., 2-3x risk). However, the paper notes that the top 1-5% of PRS carriers often have risks equivalent to monogenic mutation carriers.

Q9: What is the “Number Needed to Screen” (NNS) implication?

  • Answer: PRS improves the efficiency of screening. By screening high-risk people earlier, the NNS drops (fewer people need to be screened to save one life). By screening low-risk people less, we avoid false positives.

Q10: Is there any safety risk to knowing my PRS?

  • Answer: Psychological stress (the “Nocebo” effect). If you know you are high risk for Alzheimer’s or Heart Disease, you might perceive normal symptoms as catastrophic. Ensure you have a plan to act on the data before you get it.