Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate

He, Maoxian; Zuo, Xian Bo; Liu, H; Wang, W; Zhang, Y; Fu, Yuchuan; Zhen, Qi; Yu, Yang; Pan, Yongchu; Qin, Chuanqi; Li, B; Yang, Ruihuan; Wu, Juan; Huang, Zhengdong; Ge, Huiyao; Wu, Hao; Xu, Qiang; Zuo, Yining; Chen, W; Qin, Yue; Liu, Z; Chen, S; Zhang, H; Zhou, Fusheng; Yan, Hansong; Chen, G; Liang, Bo; Cornell, Robert A.; Zong, Liu; Wang, Lei; Zou, Derong; Sun, Liang; Bian, Zhuan

doi:10.1177/0022034520943867

Cited by 17 publications

(23 citation statements)

References 33 publications

(42 reference statements)

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“…CL/P and CP have been historically analyzed separately [9][10][11][12]. While genetic studies have identified nearly 40 genetic regions (or loci) as significantly associated with risk to CL/P, fewer, around 10 loci, have been identified for CP [2,[13][14][15]. The findings for CP have mostly been identified in the Han Chinese population [15].…”

Section: Introductionmentioning

confidence: 99%

“…While genetic studies have identified nearly 40 genetic regions (or loci) as significantly associated with risk to CL/P, fewer, around 10 loci, have been identified for CP [2,[13][14][15]. The findings for CP have mostly been identified in the Han Chinese population [15]. These genetic studies, ranging from candidate gene approaches to genome-wide studies along with analysis of animal models, have provided insights into the genetic etiology of nonsyndromic OFCs [16].…”

Section: Introductionmentioning

confidence: 99%

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Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios

et al. 2021

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Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts– the most common craniofacial birth defects in humans– are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 × 10−8, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10−6, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios

et al. 2021

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“…Genome-wide association studies (GWAS) using both casecontrol (Birnbaum et al, 2009;Mangold et al, 2010) and caseparent trio designs (Beaty et al, 2010(Beaty et al, , 2011(Beaty et al, , 2013Leslie et al, 2016a) have identified multiple genetic risk factors for OFCs. There have been multiple GWAS for CL/P (Birnbaum et al, 2009;Grant et al, 2009;Beaty et al, 2010;Mangold et al, 2010;Camargo et al, 2012;Sun et al, 2015;Wolf et al, 2015;Leslie et al, 2016a;Yu et al, 2017;Butali et al, 2019;Huang et al, 2019), two genome-wide meta-analysis of CL/P (Ludwig et al, 2012;Leslie et al, 2017), and four GWAS of CP (Beaty et al, 2011;Leslie et al, 2016b;Butali et al, 2019;He et al, 2020). These studies have revealed a complex genetic architecture controlling risk to OFCs.…”

Section: Introductionmentioning

confidence: 99%

“…More than 40 different genes or regions have yielded genomewide significant associations with risk to CL/P from multiple populations, while one gene (GRHL3) has been clearly identified as associated with risk to CP [largely limited to populations of European ancestry (Leslie et al, 2016b)]. A recent case-control study of Han Chinese CP cases and controls also identified the region on chromosome 15q24.3 as associated with risk of CP (He et al, 2020). Of these recognized risk genes achieving genome-wide significance, four regions (IRF6 on 1q32-41, the gene desert on 8q24, markers on 10q25.3 and on 17q22) can explain about a quarter of the estimated heritability in risk to CL/P based on twin and family studies (Beaty et al, 2016;Lupo et al, 2019), which has been estimated to be around 90% for both CL/P and CP based on twin registry data in European populations (Grosen et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft

Zhang

Venkataraghavan

Hetmanski

et al. 2021

Front. Cell Dev. Biol.

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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.

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“…CL/P and CP have been historically analyzed separately 9–12 . While genetic studies have identified nearly 40 genetic regions (or loci) as significantly associated with risk to CL/P, fewer, around 10 loci, have been identified for CP 2,13–15 . The findings for CP have mostly been identified in the Han Chinese population 15 .…”

Section: Introductionmentioning

confidence: 99%

Pleiotropy method identifies genetic overlap between orofacial clefts at multiple loci from GWAS of multi-ethnictrios

Ray

Venkataraghavan

Zhang

et al. 2020

Preprint

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Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). While nearly forty risk genes have been identified for CL/P, few risk genes are known for CP. We used a new statistical method, PLACO, to identify genetic variants influencing risk of both CL/P and CP. In a combined multi-ethnic genome-wide study of 2,771 CL/P and 611 CP case-parent trios, we discovered 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. We replicated the shared genetic etiology of subtypes underlying CL/P, and further discovered loci of genetic overlap exhibiting etiologic differences. In summary, we found evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.

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Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate

Cited by 17 publications

References 33 publications

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios

Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft

Pleiotropy method identifies genetic overlap between orofacial clefts at multiple loci from GWAS of multi-ethnictrios

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