Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome
| Autor: | Cristina E. Trevino, Aaron M. Holleman, Holly Corbitt, Cheryl L. Maslen, Tracie C. Rosser, David J. Cutler, H. Richard Johnston, Benjamin L. Rambo-Martin, Jai Oberoi, Kenneth J. Dooley, George T. Capone, Roger H. Reeves, Heather J. Cordell, Bernard D. Keavney, A.J. Agopian, Elizabeth Goldmuntz, Peter J. Gruber, James E. O’Brien, Douglas C. Bittel, Lalita Wadhwa, Clifford L. Cua, Ivan P. Moskowitz, Jennifer G. Mulle, Michael P. Epstein, Stephanie L. Sherman, Michael E. Zwick |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Risk 0301 basic medicine Down syndrome Population lcsh:Medicine Aneuploidy Cell Cycle Proteins 030105 genetics & heredity Article Genomic analysis Cohort Studies 03 medical and health sciences Antigens Neoplasm Genetic variation medicine Humans DNA sequencing lcsh:Science Receptor Notch4 Author Correction education Exome sequencing Genetics education.field_of_study Multidisciplinary Whole Genome Sequencing business.industry Heart Septal Defects lcsh:R Infant Newborn Infant Cardiovascular genetics Odds ratio medicine.disease Cytoskeletal Proteins 030104 developmental biology Congenital heart defects Cohort lcsh:Q Female Down Syndrome business Imputation (genetics) Genome-Wide Association Study |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-74650-4 |
| Popis: | Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS. |
| Databáze: | OpenAIRE |
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