The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome
- M. Reza Sailani1,
- Periklis Makrythanasis1,
- Armand Valsesia2,
- Federico Santoni1,
- Samuel Deutsch1,
- Konstantin Popadin1,
- Christelle Borel1,
- Eugenia Migliavacca1,
- Andrew J Sharp1,
- Genevieve Duriaux Sail1,
- Emilie Falconnet1,
- Kelly Rabionet3,
- Clara Serra Juhé4,
- Stefano Vicari5,
- Daniela Laux6,
- Yann Grattau7,
- Guy Dembour8,
- Andre Megarbane7,
- Renaud Touraine9,
- Samantha Stora7,
- Sofia Kitsiou10,
- Helena Fryssira10,
- Chariklia Chatzisevastou-loukidou10,
- Emmanouel Kanavakis10,
- Giuseppe Merla11,
- Damien Bonnet6,
- Luis A. Pérez-Jurado4,
- Xavier Estivill3,
- Jean M. Delabar12 and
- Stylianos E. Antonarakis1,13
- 1 University of Geneva;
- 2 University of Lausanne;
- 3 Centre for Genomic Regulation;
- 4 Universitat Pompeu Fabra;
- 5 Children's Hospital Bambino Gesù;
- 6 University Paris Descartes;
- 7 Institut Jerome Lejeune;
- 8 Cliniques universitaires Saint-Luc;
- 9 CHU de Saint-Etienne;
- 10 University of Athens;
- 11 IRCCS;
- 12 Universite Paris Diderot
- ↵* Corresponding author; email: stylianos.antonarakis{at}unige.ch
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 study 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 which 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 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, 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.
- Received August 20, 2012.
- Accepted May 22, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
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