TY - JOUR
T1 - Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft
AU - Zhang, Wanying
AU - Venkataraghavan, Sowmya
AU - Hetmanski, Jacqueline B.
AU - Leslie, Elizabeth J.
AU - Marazita, Mary L.
AU - Feingold, Eleanor
AU - Weinberg, Seth M.
AU - Ruczinski, Ingo
AU - Taub, Margaret A.
AU - Scott, Alan F.
AU - Ray, Debashree
AU - Beaty, Terri H.
N1 - Funding Information:
This work was supported for the study entitled “International Consortium to Identify Genes and Interactions Controlling Oral Clefts” was provided by several previous grants from the National Institute of Dental and Craniofacial Research (NIDCR). Data and samples were drawn from several studies awarded to members of this consortium. Funding to support original data collection, previous genotyping, and analysis came from several sources to individual investigators. Funding for individual investigators include the following: R21-DE-013707 and R0l-DE-014581 (TB); R03-DE-027121 (TB, MT); R37-DE-08559 and PS0-DE-016215 (Murray, MM) and the Iowa Comprehensive Program to Investigate Craniofacial and Dental Anomalies (Murray); R0l-DE-09886 (MM); R0l-DE-012472 (MM); R0l-DE-014677 (MM); R0l-DE-016148 (MM), R03-DE-029254 (DR); R21-DE-016930 (MM); and R0l-DE-013939 (AS). Parts of this research were supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Wilcox, Lie). Additional recruitment was supported by the Smile Train Foundation for recruitment in China (Jabs, TB, Shi) and a grant from the Korean government (Jee). The genome-wide association study, also known as the Cleft Consortium, is part of the Gene Environment Association Studies (GENEVA) program of the trans-NIH Genes, Environment and Health Initiative (GEi) supported by U0l-DE-018993. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268200782096C. Funds for genotyping were provided by the NIDCR through CIDR’s NIH contract. Assistance with genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U0l-HG-004446) and by the National Center for Biotechnology Information (NCBI).
Funding Information:
We sincerely thank all the patients and families at each recruitment site for participating in this study, and we gratefully acknowledge the invaluable assistance of clinical, field, and laboratory staff who contributed to this effort over the years. Funding. This work was supported for the study entitled ?International Consortium to Identify Genes and Interactions Controlling Oral Clefts? was provided by several previous grants from the National Institute of Dental and Craniofacial Research (NIDCR). Data and samples were drawn from several studies awarded to members of this consortium. Funding to support original data collection, previous genotyping, and analysis came from several sources to individual investigators. Funding for individual investigators include the following: R21-DE-013707 and R0l-DE-014581 (TB); R03-DE-027121 (TB, MT); R37-DE-08559 and PS0-DE-016215 (Murray, MM) and the Iowa Comprehensive Program to Investigate Craniofacial and Dental Anomalies (Murray); R0l-DE-09886 (MM); R0l-DE-012472 (MM); R0l-DE-014677 (MM); R0l-DE-016148 (MM), R03-DE-029254 (DR); R21-DE-016930 (MM); and R0l-DE-013939 (AS). Parts of this research were supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Wilcox, Lie). Additional recruitment was supported by the Smile Train Foundation for recruitment in China (Jabs, TB, Shi) and a grant from the Korean government (Jee). The genome-wide association study, also known as the Cleft Consortium, is part of the Gene Environment Association Studies (GENEVA) program of the trans- NIH Genes, Environment and Health Initiative (GEi) supported by U0l-DE-018993. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268200782096C. Funds for genotyping were provided by the NIDCR through CIDR?s NIH contract. Assistance with genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U0l-HG-004446) and by the National Center for Biotechnology Information (NCBI).
Publisher Copyright:
© Copyright © 2021 Zhang, Venkataraghavan, Hetmanski, Leslie, Marazita, Feingold, Weinberg, Ruczinski, Taub, Scott, Ray and Beaty.
PY - 2021/4/16
Y1 - 2021/4/16
N2 - Two large studies of case–parent trios ascertained through a proband with a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate, cleft lip alone, or cleft palate alone) were used to test for possible gene–environment (G × E) interaction between genome-wide markers (both observed and imputed) and self-reported maternal exposure to smoking, alcohol consumption, and multivitamin supplementation during pregnancy. The parent studies were as follows: GENEVA, which included 1,939 case–parent trios recruited largely through treatment centers in Europe, the United States, and Asia, and 1,443 case–parent trios from the Pittsburgh Orofacial Cleft Study (POFC) also ascertained through a proband with an OFC including three major racial/ethnic groups (European, Asian, and Latin American). Exposure rates to these environmental risk factors (maternal smoking, alcohol consumption, and multivitamin supplementation) varied across studies and among racial/ethnic groups, creating substantial differences in power to detect G × E interaction, but the trio design should minimize spurious results due to population stratification. The GENEVA and POFC studies were analyzed separately, and a meta-analysis was conducted across both studies to test for G × E interaction using the 2 df test of gene and G × E interaction and the 1 df test for G × E interaction alone. The 2 df test confirmed effects for several recognized risk genes, suggesting modest G × E effects. This analysis did reveal suggestive evidence for G × Vitamin interaction for CASP9 on 1p36 located about 3 Mb from PAX7, a recognized risk gene. Several regions gave suggestive evidence of G × E interaction in the 1 df test. For example, for G × Smoking interaction, the 1 df test suggested markers in MUSK on 9q31.3 from meta-analysis. Markers near SLCO3A1 also showed suggestive evidence in the 1 df test for G × Alcohol interaction, and rs41117 near RETREG1 (a.k.a. FAM134B) also gave suggestive significance in the meta-analysis of the 1 df test for G × Vitamin interaction. While it remains quite difficult to obtain definitive evidence for G × E interaction in genome-wide studies, perhaps due to small effect sizes of individual genes combined with low exposure rates, this analysis of two large case–parent trio studies argues for considering possible G × E interaction in any comprehensive study of complex and heterogeneous disorders such as OFC.
AB - Two large studies of case–parent trios ascertained through a proband with a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate, cleft lip alone, or cleft palate alone) were used to test for possible gene–environment (G × E) interaction between genome-wide markers (both observed and imputed) and self-reported maternal exposure to smoking, alcohol consumption, and multivitamin supplementation during pregnancy. The parent studies were as follows: GENEVA, which included 1,939 case–parent trios recruited largely through treatment centers in Europe, the United States, and Asia, and 1,443 case–parent trios from the Pittsburgh Orofacial Cleft Study (POFC) also ascertained through a proband with an OFC including three major racial/ethnic groups (European, Asian, and Latin American). Exposure rates to these environmental risk factors (maternal smoking, alcohol consumption, and multivitamin supplementation) varied across studies and among racial/ethnic groups, creating substantial differences in power to detect G × E interaction, but the trio design should minimize spurious results due to population stratification. The GENEVA and POFC studies were analyzed separately, and a meta-analysis was conducted across both studies to test for G × E interaction using the 2 df test of gene and G × E interaction and the 1 df test for G × E interaction alone. The 2 df test confirmed effects for several recognized risk genes, suggesting modest G × E effects. This analysis did reveal suggestive evidence for G × Vitamin interaction for CASP9 on 1p36 located about 3 Mb from PAX7, a recognized risk gene. Several regions gave suggestive evidence of G × E interaction in the 1 df test. For example, for G × Smoking interaction, the 1 df test suggested markers in MUSK on 9q31.3 from meta-analysis. Markers near SLCO3A1 also showed suggestive evidence in the 1 df test for G × Alcohol interaction, and rs41117 near RETREG1 (a.k.a. FAM134B) also gave suggestive significance in the meta-analysis of the 1 df test for G × Vitamin interaction. While it remains quite difficult to obtain definitive evidence for G × E interaction in genome-wide studies, perhaps due to small effect sizes of individual genes combined with low exposure rates, this analysis of two large case–parent trio studies argues for considering possible G × E interaction in any comprehensive study of complex and heterogeneous disorders such as OFC.
KW - case-parent trio design
KW - gene-environment interaction
KW - genome-wide association study
KW - maternal smoking
KW - maternal vitamin supplementation
KW - oral clefts
KW - orofacial clefts
UR - http://www.scopus.com/inward/record.url?scp=85104959885&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104959885&partnerID=8YFLogxK
U2 - 10.3389/fcell.2021.621018
DO - 10.3389/fcell.2021.621018
M3 - Article
C2 - 33937227
AN - SCOPUS:85104959885
SN - 2296-634X
VL - 9
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 621018
ER -