A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

Nembhard, Wendy N.; Tang, Xinyu; Li, Jingyun; MacLeod, Stewart L.; Levy, Joseph; Schaefer, Gerald; Hobbs, Charlotte A.

doi:10.1002/ajmg.a.38611

Cited by 8 publications

(12 citation statements)

References 76 publications

(83 reference statements)

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“…is known about the role of paternally-related genetic variants in outcomes of pregnancy, including their roles in CHD etiology [51]. We observed no statistically significant increased risk of OHDs for infants who inherited a paternally-derived copy of variant alleles in genes involved in folate, homocysteine, or transsulfuration pathways compared to infants who inherited a maternal copy of the variant allele.…”

Section: Plos Geneticscontrasting

confidence: 65%

“…In this study, we determined the parent-of-origin effects for genetic variants in folate, homocysteine, and transsulfuration pathway genes and occurrence of OHDs in offspring. The majority of published studies have investigated the effects of maternal genetic variants and environmental factors on the occurrence of CHDs in general [ 12 , 55 – 57 ]; however, much less is known about the role of paternally-related genetic variants in outcomes of pregnancy, including their roles in CHD etiology [ 51 ]. We observed no statistically significant increased risk of OHDs for infants who inherited a paternally-derived copy of variant alleles in genes involved in folate, homocysteine, or transsulfuration pathways compared to infants who inherited a maternal copy of the variant allele.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, to date (as of March 2020), only one study has assessed the influence of paternal genetic variants in folate, homocysteine, or transsulfuration pathways and CHD risk in offspring [ 51 ]. This study examined conotruncal heart defects and found less epigenetic influence on conotruncal heart defects by paternal genetic variants compared to maternal genes.…”

Section: Introductionmentioning

confidence: 99%

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Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

et al. 2021

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Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

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Section: Plos Geneticscontrasting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

et al. 2021

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“…The PoO effect occurs when a locus expressed in mothers or fathers has a causal influence on the phenotype of the infant, and it is often considered a genomic imprinting effect (Gjerdevik et al, ; Lawson, Cheverud, & Wolf, ). Some studies have detected gene PoO effects in birth defects, such as nonsyndromic orofacial clefts (Garg et al, ) and conotruncal heart defects (Nembhard et al, ). However, no study has reported PoO effects for PCP pathway genes related to the occurrence of NTDs.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in GRHL3 and risk for neural tube defects: A case–control and case–parent triad/control study

Yang

Xiao

Tian

et al. 2019

Birth Defects Research

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Background: Neural tube defects (NTDs) are the most common severe birth defects with complex etiologies. Previous studies conducted on animals have suggested that the Grhl3 gene is essential for closure of the spinal neural tube, but little evidence from human studies on the variants of GRHL3 gene has been provided, especially the common genetic variants. Methods: To investigate the relationship between common genetic variants of GRHL3 and the risk for NTDs, we performed a case-control study and a caseparent triad/control study. Fast-target enrichment sequencing was performed to screen exon regions from 503 NTD cases, and three tag SNPs (single nucleotide polymorphisms, including rs12030057, rs2486668, and rs545809) were selected according to the sequencing results. Then, Sequenom MassARRAY genotyping was performed in 757 case parents and 519 controls to obtain genotype information of the target variant sites among all NTD triads and controls. Results: The genotype distributions of all SNPs were in accordance with Hardy-Weinberg Equilibrium (HWE) in the control population. In the case-control study, significant associations were found between C27G genetic variants on rs2486668 and risk for spina bifida and encephalocele, respectively, under different genetic models.Consistently, in the case-parent triad/control study, GG genotype on rs2486668 was associated with increased risk for spina bifida, with a RR of 2.15 (95% CI:1.20-3.83). However, no parent-of-origin effect was found for any tag SNPs. Conclusion: The GRHL3 C67G missense variant may increase the risk for spina bifida and encephalocele phenotypes. K E Y W O R D Scase-parent triads, common variants, grainyhead like transcription factor 3, neural tube defects, single nucleotide polymorphisms

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“…POE have been described in congenital heart defects [86], attention deficit-hyperactivity disorder [87], testicular germ cell tumors [88], cleft lip [89], autism [90,91], language impairment [92], type II diabetes [93,94], adiposity [95], and BMI [96]. Some of these SNPs are located in proximity to imprinted genes; further evaluation is needed to determine whether all of these effects are mediated by the~100 imprinted genes in the human genome, or whether there are additional processes that affect asymmetry in the maternal and paternal genomes.…”

Section: Non-equivalence Of Maternal Vs Paternal Allelesmentioning

confidence: 99%

Evidence for germline non-genetic inheritance of human phenotypes and diseases

Senaldi

Smith-Raska

2020

Clin Epigenet

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It is becoming increasingly apparent that certain phenotypes are inherited across generations independent of the information contained in the DNA sequence, by factors in germ cells that remain largely uncharacterized. As evidence for germline non-genetic inheritance of phenotypes and diseases continues to grow in model organisms, there are fewer reports of this phenomenon in humans, due to a variety of complications in evaluating this mechanism of inheritance in humans. This review summarizes the evidence for germline-based non-genetic inheritance in humans, as well as the significant challenges and important caveats that must be considered when evaluating this process in human populations. Most reports of this process evaluate the association of a lifetime exposure in ancestors with changes in DNA methylation or small RNA expression in germ cells, as well as the association between ancestral experiences and the inheritance of a phenotype in descendants, down to great-grandchildren in some cases. Collectively, these studies provide evidence that phenotypes can be inherited in a DNA-independent manner; the extent to which this process contributes to disease development, as well as the cellular and molecular regulation of this process, remain largely undefined.

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A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

Cited by 8 publications

References 76 publications

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

Genetic variants in GRHL3 and risk for neural tube defects: A case–control and case–parent triad/control study

Evidence for germline non-genetic inheritance of human phenotypes and diseases

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