{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:57:38Z","timestamp":1793141858339,"version":"4.5.0"},"reference-count":28,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"<jats:sec id=\"ab-hoi230075-4\"><jats:title>Importance<\/jats:title><jats:p>Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi230075-5\"><jats:title>Objective<\/jats:title><jats:p>To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi230075-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi230075-7\"><jats:title>Exposures<\/jats:title><jats:p>PRS for SCAD comprised of 7 single-nucleotide variants.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi230075-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Disease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi230075-9\"><jats:title>Results<\/jats:title><jats:p>A total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted <jats:italic>P<\/jats:italic>\u2009=\u20091.96\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted <jats:italic>P<\/jats:italic>\u2009=\u20095.69\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted <jats:italic>P<\/jats:italic>\u2009=\u2009.91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted <jats:italic>P<\/jats:italic>\u2009=\u2009.001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted <jats:italic>P<\/jats:italic>\u2009=\u2009.001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi230075-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>Extreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamacardio.2023.5194","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T16:00:49Z","timestamp":1706112049000},"page":"254","source":"Crossref","is-referenced-by-count":18,"title":["Polygenic Risk in Families With Spontaneous Coronary Artery Dissection"],"prefix":"10.1001","volume":"9","author":[{"given":"Ingrid","family":"Tarr","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Hesselson","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Troup","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Young","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie-Lee","family":"Thompson","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"McGrath-Cadell","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Fatkin","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"},{"name":"Cardiology Department, St Vincent\u2019s Hospital, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally L.","family":"Dunwoodie","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W. M.","family":"Muller","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"},{"name":"Cardiology Department, St Vincent\u2019s Hospital, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siiri E.","family":"Iismaa","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason C.","family":"Kovacic","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"},{"name":"Cardiology Department, St Vincent\u2019s Hospital, Darlinghurst, Australia"},{"name":"Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Graham","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"},{"name":"Cardiology Department, St Vincent\u2019s Hospital, Darlinghurst, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Giannoulatou","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, Australia"},{"name":"University of New South Wales Sydney, Kensington, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"24","key":"hoi230075r1","doi-asserted-by":"publisher","first-page":"2358","DOI":"10.1056\/NEJMra2001524","article-title":"Spontaneous coronary-artery dissection.","volume":"383","author":"Kim","year":"2020","journal-title":"N Engl 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