{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:46:08Z","timestamp":1768567568266,"version":"3.49.0"},"posted":{"date-parts":[[2024,9,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF&gt;0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p&lt;2\u00d710\n                  <jats:sup>\u22126<\/jats:sup>\n                  ). Of these, the 1p35.1 locus (near\n                  <jats:italic>RBBP4<\/jats:italic>\n                  ) was specifically associated with ASD risk and the 5q35.2 locus (near\n                  <jats:italic>MSX2<\/jats:italic>\n                  ) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p&lt;2\u00d710\n                  <jats:sup>\u22126<\/jats:sup>\n                  ) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.\n                <\/jats:p>","DOI":"10.1101\/2024.09.06.24313183","type":"posted-content","created":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T02:35:11Z","timestamp":1725676511000},"source":"Crossref","is-referenced-by-count":2,"title":["Genome-wide association studies of Down syndrome associated congenital heart defects"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2969-415X","authenticated-orcid":false,"given":"Elizabeth R.","family":"Feldman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8887-9691","authenticated-orcid":false,"given":"Yunqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-6731","authenticated-orcid":false,"given":"David J.","family":"Cutler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracie C.","family":"Rosser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9321-0220","authenticated-orcid":false,"given":"Stephanie B.","family":"Wechsler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Sanclemente","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela L.","family":"Rachubinski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalina","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3931-0914","authenticated-orcid":false,"given":"Paresh","family":"Vyas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-6397","authenticated-orcid":false,"given":"Irene","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-8195","authenticated-orcid":false,"given":"Karen R.","family":"Rabin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8527-5027","authenticated-orcid":false,"given":"Bruce D.","family":"Gelb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9048-1941","authenticated-orcid":false,"given":"Joaquin M.","family":"Espinosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0978-5863","authenticated-orcid":false,"given":"Philip J.","family":"Lupo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J.","family":"de Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie L.","family":"Sherman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5735-1712","authenticated-orcid":false,"given":"Elizabeth J.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024091000250768000_2024.09.06.24313183v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s002469900346"},{"key":"2024091000250768000_2024.09.06.24313183v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096057"},{"key":"2024091000250768000_2024.09.06.24313183v1.3","doi-asserted-by":"crossref","unstructured":"Bakkers*, J. 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