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Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy
Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethn...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252673/ https://www.ncbi.nlm.nih.gov/pubmed/32407400 http://dx.doi.org/10.1371/journal.pgen.1008747 |
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author | Tekola-Ayele, Fasil Zhang, Cuilin Wu, Jing Grantz, Katherine L. Rahman, Mohammad L. Shrestha, Deepika Ouidir, Marion Workalemahu, Tsegaselassie Tsai, Michael Y. |
author_facet | Tekola-Ayele, Fasil Zhang, Cuilin Wu, Jing Grantz, Katherine L. Rahman, Mohammad L. Shrestha, Deepika Ouidir, Marion Workalemahu, Tsegaselassie Tsai, Michael Y. |
author_sort | Tekola-Ayele, Fasil |
collection | PubMed |
description | Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10(-8); log(10)BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10(-8)), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132. |
format | Online Article Text |
id | pubmed-7252673 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-72526732020-06-10 Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy Tekola-Ayele, Fasil Zhang, Cuilin Wu, Jing Grantz, Katherine L. Rahman, Mohammad L. Shrestha, Deepika Ouidir, Marion Workalemahu, Tsegaselassie Tsai, Michael Y. PLoS Genet Research Article Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10(-8); log(10)BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10(-8)), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132. Public Library of Science 2020-05-14 /pmc/articles/PMC7252673/ /pubmed/32407400 http://dx.doi.org/10.1371/journal.pgen.1008747 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Tekola-Ayele, Fasil Zhang, Cuilin Wu, Jing Grantz, Katherine L. Rahman, Mohammad L. Shrestha, Deepika Ouidir, Marion Workalemahu, Tsegaselassie Tsai, Michael Y. Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
title | Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
title_full | Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
title_fullStr | Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
title_full_unstemmed | Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
title_short | Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
title_sort | trans-ethnic meta-analysis of genome-wide association studies identifies maternal itpr1 as a novel locus influencing fetal growth during sensitive periods in pregnancy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252673/ https://www.ncbi.nlm.nih.gov/pubmed/32407400 http://dx.doi.org/10.1371/journal.pgen.1008747 |
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