A genome‐wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Rashkin, Sara R.; Cleves, Mario A.; Shaw, Gary M.; Nembhard, Wendy N.; Nestoridi, Eirini; Jenkins, Mary M.; Romitti, Paul A.; Lou, Xiang‐Yang; Browne, Marilyn L.; Mitchell, Laura E.; Olshan, Andrew F.; Lomangino, Kevin; Bhattacharyya, Sudeepa; Witte, John S.; Hobbs, Charlotte A.

doi:10.1002/ajmg.a.62759

Cited by 4 publications

(3 citation statements)

References 54 publications

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“…Information regarding maternal exposures and lifestyle factors hypothesized to impact organogenesis were obtained through structured computer‐assisted maternal interviews conducted by research staff. Once a woman completed the interview, DNA samples of her child, the biological father, and herself were collected (Rashkin et al, 2022). Funding for a genome wide association study was awarded to CAH, PI, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.…”

Section: Methodsmentioning

confidence: 99%

“…Samples from five NBDPS sites (Arkansas, California, Georgia, Iowa, and Texas) were included as the Phase I sample of the GWAS, and samples from the other four NBDPS sites (Massachusetts, New York, North Carolina, and Utah) were included as the Phase II sample. Details of the sample collection and quality controls can be found elsewhere (Rashkin et al, 2022).…”

Section: Application To Chd Gwas Datamentioning

confidence: 99%

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A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Huang,

Lyu,

Liu

et al. 2023

Genetic Epidemiology

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The risk of congenital heart defects (CHDs) may be influenced by maternal genes, fetal genes, and their interactions. Existing methods commonly test the effects of maternal and fetal variants one‐at‐a‐time and may have reduced statistical power to detect genetic variants with low minor allele frequencies. In this article, we propose a gene‐based association test of interactions for maternal–fetal genotypes (GATI‐MFG) using a case‐mother and control‐mother design. GATI‐MFG 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‐MFG had improved statistical power over alternative methods, such as the single‐variant test and functional data analysis (FDA) under various disease scenarios. We further applied GATI‐MFG to a two‐phase genome‐wide association study of CHDs for the testing of both common variants and rare variants using 947 CHD case mother–infant pairs and 1306 control mother–infant pairs from the National Birth Defects Prevention Study (NBDPS). After Bonferroni adjustment for 23,035 genes, two genes on chromosome 17, TMEM107 (p = 1.64e−06) and CTC1 (p = 2.0e−06), were identified for significant association with CHD in common variants analysis. Gene TMEM107 regulates ciliogenesis and ciliary protein composition and was found to be associated with heterotaxy. Gene CTC1 plays an essential role in protecting telomeres from degradation, which was suggested to be associated with cardiogenesis. Overall, GATI‐MFG outperformed the single‐variant test and FDA in the simulations, and the results of application to NBDPS samples are consistent with existing literature supporting the association of TMEM107 and CTC1 with CHDs.

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Section: Methodsmentioning

confidence: 99%

Section: Application To Chd Gwas Datamentioning

confidence: 99%

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Huang,

Lyu,

Liu

et al. 2023

Genetic Epidemiology

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show abstract

“…There is also evidence, albeit incomplete, that common genetic variants contribute to left sided congenital heart defects [ 47 , 48 , 49 , 50 , 51 ]. Genome wide association studies have found loci that meet standard statistical criteria for significance, but the loci identified have not yet overlapped or been strongly validated.…”

Section: Complex Inheritancementioning

confidence: 99%

Considering the Genetic Architecture of Hypoplastic Left Heart Syndrome

Belmont

2022

JCDD

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Hypoplastic left heart syndrome (HLHS) is among the most severe cardiovascular malformations and understanding its causes is crucial to making progress in prevention and treatment. Genetic analysis is a broadly useful tool for dissecting complex causal mechanisms and it is playing a significant role in HLHS research. However, unlike classical Mendelian disorders where a relatively small number of genes are largely determinative of the occurrence and severity of the disease, the picture in HLHS is complex. De novo single-gene and copy number variant (CNV) disorders make an important contribution, but there is emerging evidence for causal contributions from lower penetrance and common variation. Integrating this emerging knowledge into clinical diagnostics and translating the findings into effective prevention and treatment remain challenges for the future.

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Sex-Specific Whole-Transcriptome Analysis in the Cerebral Cortex of FAE Offspring

Mishra

Shrinath

Rao

et al. 2023

Cells

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Fetal alcohol spectrum disorders (FASDs) are associated with systemic inflammation and neurodevelopmental abnormalities. Several candidate genes were found to be associated with fetal alcohol exposure (FAE)-associated behaviors, but a sex-specific complete transcriptomic analysis was not performed at the adult stage. Recent studies have shown that they are regulated at the developmental stage. However, the sex-specific role of RNA in FAE offspring brain development and function has not been studied yet. Here, we carried out the first systematic RNA profiling by utilizing a high-throughput transcriptomic (RNA-seq) approach in response to FAE in the brain cortex of male and female offspring at adulthood (P60). Our RNA-seq data analysis suggests that the changes in RNA expression in response to FAE are marked sex-specific. We show that the genes Muc3a, Pttg1, Rec8, Clcnka, Capn11, and pnp2 exhibit significantly higher expression in the male offspring than in the female offspring at P60. FAE female mouse brain sequencing data also show an increased expression of Eno1, Tpm3, and Pcdhb2 compared to male offspring. We performed a pathway analysis using a commercial software package (Ingenuity Pathway Analysis). We found that the sex-specific top regulator genes (Rictor, Gaba, Fmri, Mlxipl) are highly associated with eIF2 (translation initiation), synaptogenesis (the formation of synapses between neurons in the nervous system), sirtuin (metabolic regulation), and estrogen receptor (involved in obesity, aging, and cancer) signaling. Taken together, our transcriptomic results demonstrate that FAE differentially alters RNA expression in the adult brain in a sex-specific manner.

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A genome‐wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Cited by 4 publications

References 54 publications

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Considering the Genetic Architecture of Hypoplastic Left Heart Syndrome

Sex-Specific Whole-Transcriptome Analysis in the Cerebral Cortex of FAE Offspring

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