{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T20:33:53Z","timestamp":1768595633827,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 HL007873"],"award-info":[{"award-number":["T32 HL007873"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F30 HL136077"],"award-info":[{"award-number":["F30 HL136077"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL105857"],"award-info":[{"award-number":["R01 HL105857"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["Established Investigator Award"],"award-info":[{"award-number":["Established Investigator Award"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+\/\u2212 mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G\u00d7GNkx) and higher-order (G\u00d7G\u00d7GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G\u00d7GNkx effects, while the loci for severe, atrioventricular septal defects exert large G\u00d7GNkx and G\u00d7G\u00d7GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G\u00d7G\u00d7GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G\u00d7G\u00d7GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved.<\/jats:p>","DOI":"10.3390\/genes12091368","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T08:42:32Z","timestamp":1630399352000},"page":"1368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost"],"prefix":"10.3390","volume":"12","author":[{"given":"Ehiole","family":"Akhirome","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suk D.","family":"Regmi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel A.","family":"Magnan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelson","family":"Ugwu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yidan","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire E.","family":"Schulkey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James M.","family":"Cheverud","sequence":"additional","affiliation":[{"name":"Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick Y.","family":"Jay","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/S0735-1097(02)01886-7","article-title":"The incidence of congenital heart disease","volume":"39","author":"Hoffman","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hoffman, J.I.E. (2009). The Natural and Unnatural History of Congenital Heart Disease, Wiley-Blackwell.","DOI":"10.1002\/9781444314045"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/GIM.0b013e3181634867","article-title":"Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project","volume":"10","author":"Freeman","year":"2008","journal-title":"Genet. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1136\/jmg.34.10.798","article-title":"Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study","volume":"34","author":"Ryan","year":"1997","journal-title":"J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1172\/JCI8154","article-title":"Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways","volume":"104","author":"Benson","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1016\/j.jacc.2016.08.064","article-title":"Cardiac Phenotype and Long-Term Follow-Up of Patients With Mutations in NKX2-5 Gene","volume":"68","author":"Maury","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1253\/circj.CJ-16-1343","article-title":"The Complex Genetic Basis of Congenital Heart Defects","volume":"81","author":"Akhirome","year":"2017","journal-title":"Circ. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1161\/CIRCULATIONAHA.109.887687","article-title":"Heterogeneity of genetic modifiers ensures normal cardiac development","volume":"121","author":"Winston","year":"2010","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"46438","DOI":"10.1038\/srep46438","article-title":"Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart","volume":"7","author":"Panzer","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1161\/CIRCGENETICS.111.961136","article-title":"Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation","volume":"5","author":"Winston","year":"2012","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/ng.3800","article-title":"Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast","volume":"49","author":"Forsberg","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nature12678","article-title":"Genetic incompatibilities are widespread within species","volume":"504","author":"Zhou","year":"2013","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1534\/genetics.117.300406","article-title":"Polygenicity and Epistasis Underlie Fitness-Proximal Traits in the Caenorhabditis elegans Multiparental Experimental Evolution (CeMEE) Panel","volume":"207","author":"Noble","year":"2017","journal-title":"Genetics"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hill, W.G., Goddard, M.E., and Visscher, P.M. (2008). Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet., 4.","DOI":"10.1371\/journal.pgen.1000008"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wilkins, J.F., McHale, P.T., Gervin, J., and Lander, A.D. (2016). Survival of the Curviest: Noise-Driven Selection for Synergistic Epistasis. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1006003"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.cell.2016.06.047","article-title":"Genotypic Context and Epistasis in Individuals and Populations","volume":"166","author":"Sackton","year":"2016","journal-title":"Cell"},{"key":"ref_17","first-page":"1959","article-title":"Perspective: Evolution and detection of genetic robustness","volume":"57","author":"Hermisson","year":"2003","journal-title":"Evolution"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1146\/annurev-ecolsys-120213-091705","article-title":"On the Nature and Evolutionary Impact of Phenotypic Robustness Mechanisms","volume":"45","author":"Siegal","year":"2014","journal-title":"Annu. Rev. Ecol. Evol. Syst."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1242\/dev.126.6.1269","article-title":"The cardiac homeobox gene Csx\/Nkx2.5 lies genetically upstream of multiple genes essential for heart development","volume":"126","author":"Tanaka","year":"1999","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1093\/genetics\/141.3.1199","article-title":"Advanced intercross lines, an experimental population for fine genetic mapping","volume":"141","author":"Darvasi","year":"1995","journal-title":"Genetics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/bioinformatics\/btg112","article-title":"R\/qtl: QTL mapping in experimental crosses","volume":"19","author":"Broman","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/ng.2310","article-title":"Genome-wide efficient mixed-model analysis for association studies","volume":"44","author":"Zhou","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1046\/j.1365-2540.2001.00901.x","article-title":"A simple correction for multiple comparisons in interval mapping genome scans","volume":"87","author":"Cheverud","year":"2001","journal-title":"Heredity (Edinb)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/gepi.20563","article-title":"Multiple testing corrections for imputed SNPs","volume":"35","author":"Gao","year":"2011","journal-title":"Genet. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1534\/genetics.114.167056","article-title":"High-resolution genetic mapping of complex traits from a combined analysis of F2 and advanced intercross mice","volume":"198","author":"Parker","year":"2014","journal-title":"Genetics"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cheng, R., Abney, M., Palmer, A.A., and Skol, A.D. (2011). QTLRel: an R package for genome-wide association studies in which relatedness is a concern. BMC Genet., 12.","DOI":"10.1186\/1471-2156-12-66"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhou, X., Carbonetto, P., and Stephens, M. (2013). Polygenic modeling with bayesian sparse linear mixed models. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003264"},{"key":"ref_28","unstructured":"Falconer, D.S., and Mackay, T.F.C. (1996). Introduction to Quantitative Genetics, Pearson. [4th ed.]."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.ajhg.2016.02.012","article-title":"Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models","volume":"98","author":"Chen","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1093\/genetics\/139.3.1455","article-title":"Epistasis and its contribution to genetic variance components","volume":"139","author":"Cheverud","year":"1995","journal-title":"Genetics"},{"key":"ref_31","unstructured":"Sokal, R.R., and Rohlf, F.J. (1995). Biometry: The Principles and Practices of Statistics in Biological Research, WH Freeman and Co.. [3rd ed.]."},{"key":"ref_32","first-page":"665","article-title":"ppcor: An R Package for a Fast Calculation to Semi-partial Correlation Coefficients","volume":"22","author":"Kim","year":"2015","journal-title":"Commun. Stat. Appl. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/biomet\/30.1-2.81","article-title":"A new measure of rank correlation","volume":"30","author":"Kendall","year":"1938","journal-title":"Biometrika"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/biomet\/32.3-4.277","article-title":"Partial rank correlation","volume":"32","author":"Kendall","year":"1942","journal-title":"Biometrika"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1126\/science.281.5373.108","article-title":"Congenital heart disease caused by mutations in the transcription factor NKX2-5","volume":"281","author":"Schott","year":"1998","journal-title":"Science"},{"key":"ref_36","first-page":"87","article-title":"Nothing in Biology Makes Sense except in the Light of Evolution","volume":"75","author":"Dobzhansky","year":"1973","journal-title":"Am. Biol. Teach."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/ng.3970","article-title":"Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands","volume":"49","author":"Jin","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/ng.3627","article-title":"Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing","volume":"48","author":"Sifrim","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/gim.2015.60","article-title":"Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect","volume":"18","author":"Manickaraj","year":"2016","journal-title":"Genet. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nature12141","article-title":"De novo mutations in histone-modifying genes in congenital heart disease","volume":"498","author":"Zaidi","year":"2013","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1093\/genetics\/33.6.588","article-title":"Genetics of natural populations. XVIII. Experiments on chromosomes of Drosophila pseudoobscura from different geographic regions","volume":"33","author":"Dobzhansky","year":"1948","journal-title":"Genetics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/genetics\/35.3.288","article-title":"Genetics of natural populations. XIX. Origin of heterosis through natural selection in populations of Drosophila pseudoobscura","volume":"35","author":"Dobzhansky","year":"1950","journal-title":"Genetics"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tyler, A.L., Donahue, L.R., Churchill, G.A., and Carter, G.W. (2016). Weak Epistasis Generally Stabilizes Phenotypes in a Mouse Intercross. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005805"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1534\/g3.115.026773","article-title":"Latitudinal Clines of the Human Vitamin D Receptor and Skin Color Genes","volume":"6","author":"Tiosano","year":"2016","journal-title":"G3 (Bethesda)"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Chen, A., Liu, Y., Williams, S.M., Morris, N., and Buchner, D.A. (2017). Widespread epistasis regulates glucose homeostasis and gene expression. PLoS Genet., 13.","DOI":"10.1101\/132175"},{"key":"ref_46","unstructured":"Wagner, A. (2005). Robustness and Evolvability in Living Systems, Princeton University Press."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:53:08Z","timestamp":1760165588000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,31]]},"references-count":46,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["genes12091368"],"URL":"https:\/\/doi.org\/10.3390\/genes12091368","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,31]]}}}