Joint associations of cardiovascular polygenic risk and a health-related risk profile with incident cardiovascular disease among adults with depression: a UK Biobank study.
Lim Y & Kwon R • Frontiers in endocrinology • 2026
Among adults with depression, inherited cardiovascular susceptibility was more evident in near-term (0–5 year) CVD risk, whereas adverse health-related risk profiles were more evident in later (5–10 year) risk among participants with intermediate or high polygenic risk scores.
Key Findings
Results
High polygenic risk score combined with a favorable health-related profile was associated with significantly higher CVD risk during years 0–5 compared to low PRS plus a favorable profile.
Adjusted hazard ratio (aHR) of 2.00 (95% CI, 1.15–3.47) for high PRS plus favorable profile versus low PRS plus favorable profile
304 incident CVD events occurred during the 0–5 year period
The study identified 3,446 participants with depression from the UK Biobank
CVD PRS was standardized and categorized into low, intermediate, and high tertiles
Results
During years 5–10, both intermediate and high PRS combined with an adverse health-related profile were associated with higher CVD risk compared to low PRS plus a favorable profile.
Intermediate PRS plus adverse profile: aHR 2.02 (95% CI, 1.08–3.77)
High PRS plus adverse profile: aHR 1.89 (95% CI, 1.01–3.54)
192 incident CVD events occurred during the 5–10 year landmark period
The 5–10 year landmark analysis included 3,062 participants who were alive, CVD-free, uncensored, and under observation at 5 years
Methods
The study population consisted of 3,446 UK Biobank participants with depression identified either by ICD-10 diagnosis or PHQ-9 score.
Depression was identified via ICD-10 codes recorded before recruitment (index date: recruitment assessment date) or PHQ-9 score ≥ 10 (index date: questionnaire assessment date)
Cox proportional-hazards models were used to assess incident CVD
Separate analyses were conducted for years 0–5 and years 5–10 (landmark analysis)
Methods
The health-related risk profile was constructed from five modifiable factors, with 0–1 factors defining a favorable profile and two or more factors defining an adverse profile.
The five factors included: current smoking, frequent alcohol consumption, obesity, low physical-activity frequency, and insomnia
0–1 factors present defined a 'favorable' profile
At least two factors present defined an 'adverse' profile
Results
Descriptive differences suggested inherited susceptibility played a relatively more prominent role in near-term CVD risk, while adverse health-related profiles were more evident in later-term risk among those with intermediate or high PRS.
The authors note these are 'descriptive differences' that 'may provide complementary temporal risk information'
The authors explicitly state these findings 'do not establish that the relative importance of inherited and health-related factors changed over time'
No statistically significant interaction between PRS and health-related profile was formally tested or reported as significant in the abstract
What This Means
This research examined how genetic risk for heart disease and lifestyle-related health behaviors together affect the likelihood of developing cardiovascular disease (CVD) in people who have depression. Using data from over 3,400 UK Biobank participants with depression, the researchers scored each person's inherited CVD risk using a polygenic risk score (a measure combining many genetic variants) and assessed their health behaviors across five areas: smoking, alcohol use, obesity, physical activity, and insomnia. They then tracked who developed CVD over up to 10 years.
The study found that in the first five years of follow-up, people with high genetic risk for CVD had double the risk of developing heart disease compared to those with low genetic risk — even when their health behaviors were relatively healthy. In the subsequent five-year period (years 5–10), it was the combination of intermediate or high genetic risk with unhealthy lifestyle behaviors that was most strongly associated with elevated CVD risk. This suggests that genetic susceptibility may matter more for shorter-term risk, while the accumulation of unhealthy behaviors may become increasingly important over longer time horizons, though the authors caution that these are descriptive patterns and do not conclusively prove that the relative importance of genes versus lifestyle changes over time.
For people with depression — who already face elevated cardiovascular risk — these findings suggest that both genetic predisposition and modifiable health behaviors such as smoking, physical inactivity, and poor sleep are relevant to CVD risk. This research suggests that understanding a person's genetic risk alongside their health behaviors may provide more complete information about when and how cardiovascular risk accumulates, which could potentially inform how monitoring or preventive efforts are prioritized over different time periods.
Lim Y, Kwon R. (2026). Joint associations of cardiovascular polygenic risk and a health-related risk profile with incident cardiovascular disease among adults with depression: a UK Biobank study.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2026.1934597