Cargando…

Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks

BACKGROUND: Neural tube defects (NTDs) are the second most common complex birth defect, yet, our understanding of the genetic contribution to their development remains incomplete. Two environmental factors associated with NTDs are Folate and One Carbon Metabolism (FOCM) and Glucose Homeostasis and O...

Descripción completa

Detalles Bibliográficos
Autores principales: Hillman, Paul, Baker, Craig, Hebert, Luke, Brown, Michael, Hixson, James, Ashley‐Koch, Allison, Morrison, Alanna C., Northrup, Hope, Au, Kit Sing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667334/
https://www.ncbi.nlm.nih.gov/pubmed/32960507
http://dx.doi.org/10.1002/mgg3.1495
_version_ 1783610290601984000
author Hillman, Paul
Baker, Craig
Hebert, Luke
Brown, Michael
Hixson, James
Ashley‐Koch, Allison
Morrison, Alanna C.
Northrup, Hope
Au, Kit Sing
author_facet Hillman, Paul
Baker, Craig
Hebert, Luke
Brown, Michael
Hixson, James
Ashley‐Koch, Allison
Morrison, Alanna C.
Northrup, Hope
Au, Kit Sing
author_sort Hillman, Paul
collection PubMed
description BACKGROUND: Neural tube defects (NTDs) are the second most common complex birth defect, yet, our understanding of the genetic contribution to their development remains incomplete. Two environmental factors associated with NTDs are Folate and One Carbon Metabolism (FOCM) and Glucose Homeostasis and Oxidative Stress (GHOS). Utilizing next‐generation sequencing of a large patient cohort, we identify novel candidate genes in these two networks to provide insights into NTD mechanisms. METHODS: Exome sequencing (ES) was performed in 511 patients, born with myelomeningocele, divided between European American and Mexican American ethnicities. Healthy control data from the Genome Aggregation database were ethnically matched and used as controls. Rare, high fidelity, nonsynonymous predicted damaging missense, nonsense, or canonical splice site variants in independently generated candidate gene lists for FOCM and GHOS were identified. We used a gene‐based collapsing approach to quantify mutational burden in case and controls, with the control cohort estimated using cumulative allele frequencies assuming Hardy–Weinberg equilibrium. RESULTS: We identified 45 of 837 genes in the FOCM network and 22 of 568 genes in the GHOS network as possible NTD risk genes with p < 0.05. No nominally significant risk genes were shared between ethnicities. Using a novel approach to mutational burden we identify 55 novel NTD risk associations. CONCLUSIONS: We provide a means of utilizing large publicly available sequencing datasets as controls for sequencing projects examining rare disease. This approach confirmed existing risk genes for myelomeningocele and identified possible novel risk genes. Lastly, it suggests possible distinct genetic etiologies for this malformation between different ethnicities.
format Online
Article
Text
id pubmed-7667334
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-76673342020-11-20 Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks Hillman, Paul Baker, Craig Hebert, Luke Brown, Michael Hixson, James Ashley‐Koch, Allison Morrison, Alanna C. Northrup, Hope Au, Kit Sing Mol Genet Genomic Med Original Articles BACKGROUND: Neural tube defects (NTDs) are the second most common complex birth defect, yet, our understanding of the genetic contribution to their development remains incomplete. Two environmental factors associated with NTDs are Folate and One Carbon Metabolism (FOCM) and Glucose Homeostasis and Oxidative Stress (GHOS). Utilizing next‐generation sequencing of a large patient cohort, we identify novel candidate genes in these two networks to provide insights into NTD mechanisms. METHODS: Exome sequencing (ES) was performed in 511 patients, born with myelomeningocele, divided between European American and Mexican American ethnicities. Healthy control data from the Genome Aggregation database were ethnically matched and used as controls. Rare, high fidelity, nonsynonymous predicted damaging missense, nonsense, or canonical splice site variants in independently generated candidate gene lists for FOCM and GHOS were identified. We used a gene‐based collapsing approach to quantify mutational burden in case and controls, with the control cohort estimated using cumulative allele frequencies assuming Hardy–Weinberg equilibrium. RESULTS: We identified 45 of 837 genes in the FOCM network and 22 of 568 genes in the GHOS network as possible NTD risk genes with p < 0.05. No nominally significant risk genes were shared between ethnicities. Using a novel approach to mutational burden we identify 55 novel NTD risk associations. CONCLUSIONS: We provide a means of utilizing large publicly available sequencing datasets as controls for sequencing projects examining rare disease. This approach confirmed existing risk genes for myelomeningocele and identified possible novel risk genes. Lastly, it suggests possible distinct genetic etiologies for this malformation between different ethnicities. John Wiley and Sons Inc. 2020-09-22 /pmc/articles/PMC7667334/ /pubmed/32960507 http://dx.doi.org/10.1002/mgg3.1495 Text en © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Hillman, Paul
Baker, Craig
Hebert, Luke
Brown, Michael
Hixson, James
Ashley‐Koch, Allison
Morrison, Alanna C.
Northrup, Hope
Au, Kit Sing
Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
title Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
title_full Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
title_fullStr Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
title_full_unstemmed Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
title_short Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
title_sort identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667334/
https://www.ncbi.nlm.nih.gov/pubmed/32960507
http://dx.doi.org/10.1002/mgg3.1495
work_keys_str_mv AT hillmanpaul identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT bakercraig identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT hebertluke identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT brownmichael identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT hixsonjames identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT ashleykochallison identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT morrisonalannac identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT northruphope identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks
AT aukitsing identificationofnovelcandidateriskgenesformyelomeningocelewithintheglucosehomeostasisoxidativestressandfolateonecarbonmetabolismnetworks