Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects
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 u...
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description | 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. |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0219926</identifier><identifier>PMID: 31314787</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alleles ; Analysis ; Autism ; Biology and Life Sciences ; Birth defects ; Chromatin ; Computational Biology - methods ; Congenital diseases ; Congenital heart defects ; Consortia ; Databases, Genetic ; Defects ; Developmental biology ; DNA microarrays ; Environmental science ; Epidemiology ; Female ; Genes ; Genetic aspects ; Genetic disorders ; Genetic Predisposition to Disease ; Genetic research ; Genetics ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Genomics ; Heart ; Heart Defects, Congenital - genetics ; Hospitals ; Humans ; Initiation factor eIF-4E ; Male ; Medicine ; Medicine and Health Sciences ; Molecular Sequence Annotation ; Mutation ; Nucleic acids ; Patient outcomes ; Pediatrics ; Physical Sciences ; Public health ; Research and Analysis Methods ; Risk factors ; RNA ; Splicing ; Veins & arteries</subject><ispartof>PloS one, 2019-07, Vol.14 (7), p.e0219926</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Sewda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Sewda et al 2019 Sewda et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-77e6b9b6135a93dc3b8c34a2cc02c77c9825d85435bf7ce38a432f66efb95bae3</citedby><cites>FETCH-LOGICAL-c692t-77e6b9b6135a93dc3b8c34a2cc02c77c9825d85435bf7ce38a432f66efb95bae3</cites><orcidid>0000-0002-5874-4155 ; 0000-0003-2814-7461 ; 0000-0002-8076-4726 ; 0000-0002-3302-4610 ; 0000-0002-2272-5382</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636758/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636758/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31314787$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Winlaw, David Scott</contributor><creatorcontrib>Sewda, Anshuman</creatorcontrib><creatorcontrib>Agopian, A J</creatorcontrib><creatorcontrib>Goldmuntz, Elizabeth</creatorcontrib><creatorcontrib>Hakonarson, Hakon</creatorcontrib><creatorcontrib>Morrow, Bernice E</creatorcontrib><creatorcontrib>Taylor, Deanne</creatorcontrib><creatorcontrib>Mitchell, Laura E</creatorcontrib><creatorcontrib>Pediatric Cardiac Genomics Consortium</creatorcontrib><creatorcontrib>on behalf of the Pediatric Cardiac Genomics Consortium</creatorcontrib><title>Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. 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Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. 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genetics</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Initiation factor eIF-4E</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Molecular Sequence Annotation</subject><subject>Mutation</subject><subject>Nucleic acids</subject><subject>Patient outcomes</subject><subject>Pediatrics</subject><subject>Physical Sciences</subject><subject>Public health</subject><subject>Research and Analysis Methods</subject><subject>Risk factors</subject><subject>RNA</subject><subject>Splicing</subject><subject>Veins & arteries</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1uL1DAUx4so7jr6DUQLguhDxyZpc3kRlkXXgYUFb-BTSNOTmQxtMtuk6n57M053mco-SB4STn7nf5JzybLnqFwiwtC7rR8Hp7rlzjtYlhgJgemD7BQJgguKS_Lw6HySPQlhW5Y14ZQ-zk4IIqhinJ1mPy7AQdGoAG2-Bud7KH7ZFnIVgtdWRetdHuLYWgi5cm3eQ1SFSnFvQrJ4k2vvfBxGp1WXb0ANMW_BgI7hafbIqC7As2lfZN8-fvh6_qm4vLpYnZ9dFpoKHAvGgDaioYjUSpBWk4ZrUimsdYk1Y1pwXLe8rkjdGKaBcFURbCgF04i6UUAW2cuD7q7zQU5ZCRLjWhDBGaoSsToQrVdbuRtsr4Yb6ZWVfw1-WMv0bqs7kATVKIVRHFGoWiR4qbWpK04M4gIQTVrvp2hj00OrwcVBdTPR-Y2zG7n2PyWlhLKaJ4E3k8Dgr0cIUfY2aOg65cCPh3eLVDhWJ_TVP-j9v5uotUofsM6kcii9F5VnCaIEsyS3yJb3UGm10NtUQzA22WcOb2cOiYnwO67VGIJcffn8_-zV9zn7-ohNHdPFTfDduO-0MAerA6gHH8IA5i7JqJT7CbjNhtxPgJwmILm9OC7QndNty5M_KZEA_g</recordid><startdate>20190717</startdate><enddate>20190717</enddate><creator>Sewda, Anshuman</creator><creator>Agopian, A J</creator><creator>Goldmuntz, Elizabeth</creator><creator>Hakonarson, Hakon</creator><creator>Morrow, Bernice E</creator><creator>Taylor, Deanne</creator><creator>Mitchell, Laura E</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5874-4155</orcidid><orcidid>https://orcid.org/0000-0003-2814-7461</orcidid><orcidid>https://orcid.org/0000-0002-8076-4726</orcidid><orcidid>https://orcid.org/0000-0002-3302-4610</orcidid><orcidid>https://orcid.org/0000-0002-2272-5382</orcidid></search><sort><creationdate>20190717</creationdate><title>Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects</title><author>Sewda, Anshuman ; Agopian, A J ; Goldmuntz, Elizabeth ; Hakonarson, Hakon ; Morrow, Bernice E ; Taylor, Deanne ; Mitchell, Laura E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-77e6b9b6135a93dc3b8c34a2cc02c77c9825d85435bf7ce38a432f66efb95bae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Alleles</topic><topic>Analysis</topic><topic>Autism</topic><topic>Biology and Life Sciences</topic><topic>Birth defects</topic><topic>Chromatin</topic><topic>Computational Biology - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31314787</pmid><doi>10.1371/journal.pone.0219926</doi><tpages>e0219926</tpages><orcidid>https://orcid.org/0000-0002-5874-4155</orcidid><orcidid>https://orcid.org/0000-0003-2814-7461</orcidid><orcidid>https://orcid.org/0000-0002-8076-4726</orcidid><orcidid>https://orcid.org/0000-0002-3302-4610</orcidid><orcidid>https://orcid.org/0000-0002-2272-5382</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Alleles Analysis Autism Biology and Life Sciences Birth defects Chromatin Computational Biology - methods Congenital diseases Congenital heart defects Consortia Databases, Genetic Defects Developmental biology DNA microarrays Environmental science Epidemiology Female Genes Genetic aspects Genetic disorders Genetic Predisposition to Disease Genetic research Genetics Genome-wide association studies Genome-Wide Association Study Genomes Genomics Heart Heart Defects, Congenital - genetics Hospitals Humans Initiation factor eIF-4E Male Medicine Medicine and Health Sciences Molecular Sequence Annotation Mutation Nucleic acids Patient outcomes Pediatrics Physical Sciences Public health Research and Analysis Methods Risk factors RNA Splicing Veins & arteries |
title | Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T01%3A17%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gene-based%20genome-wide%20association%20studies%20and%20meta-analyses%20of%20conotruncal%20heart%20defects&rft.jtitle=PloS%20one&rft.au=Sewda,%20Anshuman&rft.aucorp=Pediatric%20Cardiac%20Genomics%20Consortium&rft.date=2019-07-17&rft.volume=14&rft.issue=7&rft.spage=e0219926&rft.pages=e0219926-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0219926&rft_dat=%3Cgale_plos_%3EA593632719%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2259398714&rft_id=info:pmid/31314787&rft_galeid=A593632719&rft_doaj_id=oai_doaj_org_article_3151f7ca816e4d1980ccf5483f189e16&rfr_iscdi=true |