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Existing methods commonly test the effects of maternal and fetal variants one\u2010at\u2010a\u2010time and may have reduced statistical power to detect genetic variants with low minor allele frequencies. In this article, we propose a gene\u2010based association test of interactions for maternal\u2013fetal genotypes (GATI\u2010MFG) using a case\u2010mother and control\u2010mother design. GATI\u2010MFG can integrate the effects of multiple variants within a gene or genomic region and evaluate the joint effect of maternal and fetal genotypes while allowing for their interactions. In simulation studies, GATI\u2010MFG had improved statistical power over alternative methods, such as the single\u2010variant test and functional data analysis (FDA) under various disease scenarios. We further applied GATI\u2010MFG to a two\u2010phase genome\u2010wide association study of CHDs for the testing of both common variants and rare variants using 947 CHD case mother\u2013infant pairs and 1306 control mother\u2013infant pairs from the National Birth Defects Prevention Study (NBDPS). After Bonferroni adjustment for 23,035 genes, two genes on chromosome 17, <jats:italic>TMEM107<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20091.64e\u221206) and <jats:italic>CTC1<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20092.0e\u221206), were identified for significant association with CHD in common variants analysis. Gene <jats:italic>TMEM107<\/jats:italic> regulates ciliogenesis and ciliary protein composition and was found to be associated with heterotaxy. Gene <jats:italic>CTC1<\/jats:italic> plays an essential role in protecting telomeres from degradation, which was suggested to be associated with cardiogenesis. Overall, GATI\u2010MFG outperformed the single\u2010variant test and FDA in the simulations, and the results of application to NBDPS samples are consistent with existing literature supporting the association of <jats:italic>TMEM107<\/jats:italic> and <jats:italic>CTC1<\/jats:italic> with CHDs.<\/jats:p>","DOI":"10.1002\/gepi.22533","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T11:20:18Z","timestamp":1687346418000},"page":"475-495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A gene\u2010based association test of interactions for maternal\u2013fetal genotypes identifies genes associated with nonsyndromic congenital heart defects"],"prefix":"10.1002","volume":"47","author":[{"given":"Manyan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics Indiana University Bloomington Bloomington Indiana 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