| Autor: |
Feldman ER; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322., Li Y; Center for Genetic Epidemiology, Keck School of Medicine of University of Southern California, Los Angeles, CA., Cutler DJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322., Rosser TC; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322., Wechsler SB; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322., Sanclemente L; Baylor College of Medicine, Houston, TX., Rachubinski AL; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO., Elliott N; Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK., Vyas P; Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK., Roberts I; Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK., Rabin KR; Baylor College of Medicine, Houston, TX., Wagner M; Cincinnati Children's Hospital Medical Center, Cincinnati, OH., Gelb BD; Icahn School of Medicine at Mount Sinai, New York, NY., Espinosa JM; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO., Lupo PJ; Baylor College of Medicine, Houston, TX., de Smith AJ; Center for Genetic Epidemiology, Keck School of Medicine of University of Southern California, Los Angeles, CA., Sherman SL; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322., Leslie EJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322. |
| Abstrakt: |
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>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<2×10 -6 ). Of these, the 1p35.1 locus (near RBBP4 ) was specifically associated with ASD risk and the 5q35.2 locus (near MSX2 ) 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<2×10 -6 ) 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. |
