title: The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.
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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Sailani
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.forename: Armand
authors.initials: A
authors.lastname: Valsesia
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Konstantin
authors.initials: K
authors.lastname: Popadin
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.forename: Genevieve
authors.initials: G
authors.lastname: Duriaux Sail
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.forename: Kelly
authors.initials: K
authors.lastname: Rabionet
authors.forename: Clara
authors.initials: C
authors.lastname: Serra-Juhé
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicari
authors.forename: Daniela
authors.initials: D
authors.lastname: Laux
authors.forename: Yann
authors.initials: Y
authors.lastname: Grattau
authors.forename: Guy
authors.initials: G
authors.lastname: Dembour
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Renaud
authors.initials: R
authors.lastname: Touraine
authors.forename: Samantha
authors.initials: S
authors.lastname: Stora
authors.forename: Sofia
authors.initials: S
authors.lastname: Kitsiou
authors.forename: Helena
authors.initials: H
authors.lastname: Fryssira
authors.forename: Chariklia
authors.initials: C
authors.lastname: Chatzisevastou-Loukidou
authors.forename: Emmanouel
authors.initials: E
authors.lastname: Kanavakis
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D016022:Case-Control Studies; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics; D004314:Down Syndrome / Q000150:complications / Q000175:diagnosis*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C497010:ZBTB21 protein, human; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases