Heart failure & cardiomyopathies
Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies
Authors' conclusion
The findings in this study indicate that HCM and DCM risk were modified by polygenic background, which exists on an overlapping but opposing spectrum.
Study context
- Population
- Penn Medicine BioBank participants with EHR and genotyping data
- Participants
- 49,434 participants
- Exposure
- HCM and DCM polygenic scores and pathogenic variant carrier status
- Outcome
- HCM and DCM defined by EHR diagnosis and procedure codes, and echocardiogram measurements
Main finding
As reported in the abstract
Odds ratio (95% CI)P value
HCM PGS (per 1-SD increase)risk of HCM
1.8(1.6–2.0)
P = 9.6 × 10-25HCM PGS (per 1-SD increase)risk of DCM
0.69(0.64–0.74)
P = 4.3 × 10-22DCM PGS (per 1-SD increase)risk of DCM
1.6(1.5–1.7)
P = 1.7 × 10-40DCM PGS (per 1-SD increase)risk of HCM
0.69(0.63–0.76)
P = 3.0 × 10-13Per 1-SD increase, as printed
Observational data: associations, not effects.
Further findings
Echocardiographic measures, HCM PGS
| Comparison | Increase (%) (95% CI) | P value | |
|---|---|---|---|
| HCM PGS (increase) · LVEF | 1.1 (0.9–1.3) | P = 7.3 × 10-31 | |
| −1012Difference, % (linear scale) |
| Comparison | Increase (mm) (95% CI) | P value | |
|---|---|---|---|
| HCM PGS (increase) · IVS thickness | 0.18 (0.14–0.22) | P = 9.3 × 10-19 | |
| −0.100.10.20.3Difference, mm (linear scale) |
| Outcome | Increase (mm) (95% CI) | P value | |
|---|---|---|---|
| Echocardiographic measures, DCM PGS (per 1-SD increase) — DCM PGS (per 1-SD increase) · LVIDd | 1.0 (0.93–1.1) | P = 3.2 × 10-78 | |
| −0.500.511.5Difference, mm (linear scale) |
| Outcome | Estimate | P value |
|---|---|---|
| Echocardiographic measures, HCM PGS — HCM PGS (increase) · LVIDd | decrease 0.79 mm (95% CI −0.92 to −0.67) | P = 2.3 × 10-36 |
| Echocardiographic measures, DCM PGS (per 1-SD increase) — DCM PGS (per 1-SD increase) · LVEF | decrease 2.0 % (95% CI −2.2 to −1.8) | P = 3.3 × 10-83 |
| Echocardiographic measures, DCM PGS (per 1-SD increase) — DCM PGS (per 1-SD increase) · IVS; not significant | estimate −1.3 × 10⁻3 mm (95% CI −0.04 to 0.03) | P = 0.94 |
| Discrimination (AUC) gain from adding HCM or DCM PGS to age, sex and monogenic variant status — Model with PGS vs Model with age, sex, monogenic status · HCM; CrI | AUC improvement 0.043 (95% CrI 0.034–0.053) | |
| Discrimination (AUC) gain from adding HCM or DCM PGS to age, sex and monogenic variant status — Model with PGS vs Model with age, sex, monogenic status · DCM; CrI | AUC improvement 0.045 (95% CrI 0.039–0.051) |
Discrimination (AUC) gain from adding HCM or DCM PGS to age, sex and monogenic variant status
- Monogenic and polygenic risk terms had significant independent effects in combined models
Original publication
Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies. JAMA Cardiol. Published 1 February 2026. doi:10.
Summarised from the published abstract; every number is checked against it