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The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

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dc.contributor.author Sailani, M. Reza
dc.contributor.author Rabionet, Kelly
dc.contributor.author Serra Juhé, Clara, 1984-
dc.contributor.author Pérez Jurado, Luis Alberto
dc.contributor.author Estivill, Xavier, 1955-
dc.contributor.author Antonarakis, Stylianos E.
dc.date.accessioned 2015-06-09T08:10:53Z
dc.date.available 2015-06-09T08:10:53Z
dc.date.issued 2013
dc.identifier.citation Sailani MR, Makrythanasis P, Valsesia A, Santoni FA, Deutsch S, Popadin K et al. The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome. Genome Research. 2013;23:1410-21. DOI: 10.1101/gr.147991.112
dc.identifier.issn 1088-9051
dc.identifier.uri http://hdl.handle.net/10230/23770
dc.description.abstract Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21–specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.
dc.description.sponsorship The study was supported by grants from the NCCR–Frontiers in Genetics, the European AnEuploidy project, the Fondation Child Care, the SNF 144082, the ERC 249968 to S.E.A., and the Spanish Ministry of Ecomomy and Competitivity to X.E. P.M. was supported by a grant from the Bodossaki foundation. K.P. was supported by the EMBO long-term fellowship program ALTF 527-2010
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)
dc.relation.ispartof Genome Research. 2013;23:1410-21
dc.rights © 2013, Published by Cold Spring Harbor Laboratory Press. This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
dc.rights.uri http://creativecommons.org/licenses/by-nc/3.0/
dc.subject.other Malalties coronàries
dc.subject.other Down, Síndrome de -- Complicacions
dc.title The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1101/gr.147991.112
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/249968
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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