Oral Presentation GENEMAPPERS 2024

Polygenic risk scores for comorbid conditions provide insight into the genetic aetiology of spontaneous coronary artery dissections (#29)

Ingrid Tarr 1 2 , Stephanie Hesselson 1 2 , Lijiang Ma 3 , Yunkai Gao 1 2 , Paul Young 1 2 , Michael Troup 1 2 , Renee Johnson 1 2 , David WM Miller 1 2 4 , Siiri E Iismaa 1 2 , Diane Fatkin 1 2 4 , Jason C Kovacic 1 2 4 5 , Robert M Graham 1 2 4 , Eleni Giannoulatou 1 2
  1. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
  2. UNSW, Kensington, NSW, Australia
  3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  4. Cardiology Department,, St Vincent’s Hospital, Darlinghurst, NSW, Australia
  5. Icahn School of Medicine at Mount Sinai, New York, NY, USA

Background: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that affects mostly women. Other diseases such as migraine, fibromuscular dysplasia, and hypertension are frequently comorbid in SCAD cohorts. Although we have identified both common and rare genetic variants associated with SCAD, the genetic aetiology and overlap with other traits remains largely unresolved. We asked whether SCAD cases show elevated polygenic risk for comorbid conditions, with the dual aims of 1) probing the genetic relationship between traits, and 2) discovering additional SCAD-associated common variants.

Methods: A European-ancestry cohort of 289 sporadic SCAD cases and 1127 controls were genotyped. Differences in 24 polygenic risk scores (PRS) for SCAD (NPRS=1), control (NPRS=2) and comorbid conditions (Ntraits=11, NPRS=21) were assessed between cases and controls, or as stratified by comorbidity status. Additionally, variants in linkage disequilibrium with known SCAD variants were removed from PRS, to clarify whether associations represent novel insight. For pruned PRS found to be associated with SCAD, the variants comprising these PRS was individually analysed for association with SCAD.

Results: 11/21 comorbidity PRS were significantly associated with the odds of experiencing SCAD. Cases were stratifiable for 7/11 PRS, and in 4/7, signal was maintained in the subset of cases absent the comorbidity in question. Ultimately, after pruning PRS variants in linkage disequilibrium with SCAD variants, associations with blood pressure and cholesterol persisted. From blood pressure and cholesterol PRS, 3 and 2 PRS variant(s) were found to be significantly associated with SCAD for the first time.  

Conclusion: We have illustrated that previously unknown-in-SCAD variants contribute to the shared genetic aetiology of SCAD and its comorbidities and have refined our understanding of the genetic overlap between these traits.