TY - JOUR
T1 - Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects
AU - on behalf of the Pediatric Cardiac Genomics Consortium¶
AU - Sewda, Anshuman
AU - Agopian, A. J.
AU - Goldmuntz, Elizabeth
AU - Hakonarson, Hakon
AU - Morrow, Bernice E.
AU - Taylor, Deanne
AU - Mitchell, Laura E.
N1 - Publisher Copyright:
© 2019 Sewda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects.
AB - Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects.
UR - http://www.scopus.com/inward/record.url?scp=85069670903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069670903&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0219926
DO - 10.1371/journal.pone.0219926
M3 - Article
C2 - 31314787
AN - SCOPUS:85069670903
SN - 1932-6203
VL - 14
JO - PloS one
JF - PloS one
IS - 7
M1 - e0219926
ER -