Polygenic risk and genomic signals in premature coronary artery disease

Abstract

BackgroundPremature coronary artery disease (pCAD) is a distinct presentation of CAD. Using the All of Us (AoU) Research Program data, we compared pCAD with later-onset CAD across cardiometabolic, polygenic, and genome-wide domains.

MethodsWe conducted a retrospective, cross-sectional case-case analysis of All of Us Research Program (AoU) participants with established CAD. pCAD was defined as first CAD event before age 55 years in males and before age 65 in females; later-onset CAD was defined as the first CAD event at or after age threshold. Pre-index cardiometabolic measures were extracted from electronic health records and modelled with logistic regression. Using 607,719 variants, a CAD polygenic risk score (PRS) was constructed using published summary statistics and short-read whole-genome sequencing data (srWGS). Results were standardized within self-reported race groups, and evaluated overall, by race, and with a PRS x race interaction. A case-case genome-wide association study (GWAS) compared pCAD with later-onset CAD.

ResultsThe CAD cohort included 49,919 participants, including 18,455 with pCAD and 31,464 with later-onset CAD. Participants with pCAD had higher BMI, LDL cholesterol and diastolic blood pressure, and lower HDL cholesterol, serum calcium, and systolic blood pressure. Higher BMI and LDL cholesterol were positively associated with higher odds of pCAD, whereas higher HDL cholesterol, systolic blood pressure, and serum calcium were inversely associated. PRS was associated with greater odds of pCAD in the genomic models (OR per 1-SD higher PRS, 1.14; 95% CI, 1.12-1.17; P<0.001). Analyses stratified by race showed PRS association was present among White participants but was not observed among Black participants. In the case-case GWAS, one variant reached genome-wide significance at 2q24.3 (rs13383835; OR=1.20; 95% CI, 1.13-1.27; P=5.8x10-9). A total of 137 variants met an exploratory threshold of P<1x10-5.

ConclusionsPremature onset of CAD is characterized by a distinct cardiometabolic profile driven by modifiable risk factors, greater polygenic burden, and genomic signals associated with earlier disease timing. A European-derived PRS did not transfer to Black participants, who were overrepresented in pCAD. Together, these findings support pCAD as a clinically and genetically distinct presentation of CAD and highlight the need for ancestry-specific validation of genomic risk tools in diverse cohorts.

Coronary artery disease polygenic risk score and recurrent cardiovascular events after coronary artery revascularization: A UK Biobank analysis
Aman Goyal, Zhuqing Shi, Manan Pareek +10
American journal of preventive cardiology25 Jul 2026Peer-reviewedCC BY-NC-NDFull textGeneral medicineEurope PMC
Utility of a coronary artery disease polygenic risk score in a low-risk primary prevention cohort
John H. Bertot, Giorgio E.M. Melloni, James Pirruccello +6
American journal of preventive cardiology29 Jun 2026Peer-reviewedCC BY-NC-NDFull textGeneral medicineEurope PMC
Decomposing polygenic risk of coronary artery disease into distinct biological processes
J. Morze, K. Smith, M. Kierczak +12
medRxiv8 Oct 2026PreprintCC BY-NC-NDFull textHuman geneticsmedRxiv
Lipoprotein(a) and Coronary Artery Disease Polygenic Risk Scores Do Not Improve Secondary Manifestations of Arterial Disease Score Prediction of Coronary Events After Ischemic Stroke
Rahul G. Muthalaly, Sean Tan, Julian Giovannucci +6
Journal of the American Heart Association20 Oct 2026Peer-reviewedCC BY-NC-NDSurgery & anaesthesiaCrossref
Metabolic, Atherogenic, and Anthropometric Markers for Discrimination of Premature Coronary Artery Disease in a Predominantly Statin-Treated Cohort.
Seyedeh-Tarlan Mirzohreh, Samad Ghaffari, Elnaz Javanshir +6
Vascular health and risk management16 Oct 2026Peer-reviewedCC BY-NCFull textEndocrinology & metabolismEurope PMC

Cite

BibTeX RIS

BibTeX

@misc{laird2026polygenic,
  title = {{Polygenic risk and genomic signals in premature coronary artery disease}},
  author = {Colin Laird and Diensn Xing and Mohammad Nahian Ferdous Abrar and Sambodh Sinha and Anderson Dewitt and Claire White and Kalgi Modi and Md Shenuarin Bhuiyan and Arif Yurdagul and Chris Kevil and A. Wayne Orr and Oren Rom and Steven A. Conrad and Mohammad Alfrad Nobel Bhuiyan},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.23.26366138},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.23.26366138v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Polygenic risk and genomic signals in premature coronary artery disease
AU  - Colin Laird
AU  - Diensn Xing
AU  - Mohammad Nahian Ferdous Abrar
AU  - Sambodh Sinha
AU  - Anderson Dewitt
AU  - Claire White
AU  - Kalgi Modi
AU  - Md Shenuarin Bhuiyan
AU  - Arif Yurdagul
AU  - Chris Kevil
AU  - A. Wayne Orr
AU  - Oren Rom
AU  - Steven A. Conrad
AU  - Mohammad Alfrad Nobel Bhuiyan
PY  - 2026
DA  - 2026/10/23
PB  - medRxiv
DO  - 10.64898/2026.10.23.26366138
UR  - https://www.medrxiv.org/content/10.64898/2026.10.23.26366138v1
AB  - BackgroundPremature coronary artery disease (pCAD) is a distinct presentation of CAD. Using the All of Us (AoU) Research Program data, we compared pCAD with later-onset CAD across cardiometabolic, polygenic, and genome-wide domains.  MethodsWe conducted a retrospective, cross-sectional case-case analysis of All of Us Research Program (AoU) participants with established CAD. pCAD was defined as first CAD event before age 55 years in males and before age 65 in females; later-onset CAD was defined as the first CAD event at or after age threshold. Pre-index cardiometabolic measures were extracted from electronic health records and modelled with logistic regression. Using 607,719 variants, a CAD polygenic risk score (PRS) was constructed using published summary statistics and short-read whole-genome sequencing data (srWGS). Results were standardized within self-reported race groups, and evaluated overall, by race, and with a PRS x race interaction. A case-case genome-wide association study (GWAS) compared pCAD with later-onset CAD.  ResultsThe CAD cohort included 49,919 participants, including 18,455 with pCAD and 31,464 with later-onset CAD. Participants with pCAD had higher BMI, LDL cholesterol and diastolic blood pressure, and lower HDL cholesterol, serum calcium, and systolic blood pressure. Higher BMI and LDL cholesterol were positively associated with higher odds of pCAD, whereas higher HDL cholesterol, systolic blood pressure, and serum calcium were inversely associated. PRS was associated with greater odds of pCAD in the genomic models (OR per 1-SD higher PRS, 1.14; 95% CI, 1.12-1.17; P<0.001). Analyses stratified by race showed PRS association was present among White participants but was not observed among Black participants. In the case-case GWAS, one variant reached genome-wide significance at 2q24.3 (rs13383835; OR=1.20; 95% CI, 1.13-1.27; P=5.8x10-9). A total of 137 variants met an exploratory threshold of P<1x10-5.  ConclusionsPremature onset of CAD is characterized by a distinct cardiometabolic profile driven by modifiable risk factors, greater polygenic burden, and genomic signals associated with earlier disease timing. A European-derived PRS did not transfer to Black participants, who were overrepresented in pCAD. Together, these findings support pCAD as a clinically and genetically distinct presentation of CAD and highlight the need for ancestry-specific validation of genomic risk tools in diverse cohorts.
ER  -

Abstract

Related

Cite