Abstract
It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p =.000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p =.55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
| Original language | English |
|---|---|
| Pages (from-to) | 924-933 |
| Number of pages | 10 |
| Journal | Genetic Epidemiology |
| Volume | 44 |
| Issue number | 8 |
| DOIs | |
| State | Published - Nov 2020 |
| Externally published | Yes |
Keywords
- Mendelian randomization
- birth defects
- genetic epidemiology
- oral cancers
- orofacial clefts
- polygenic risk scores
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Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms. / Howe, Laurence J.; Hemani, Gibran; Lesseur, Corina et al.
In: Genetic Epidemiology, Vol. 44, No. 8, 11.2020, p. 924-933.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms
AU - Howe, Laurence J.
AU - Hemani, Gibran
AU - Lesseur, Corina
AU - Gaborieau, Valérie
AU - Ludwig, Kerstin U.
AU - Mangold, Elisabeth
AU - Brennan, Paul
AU - Ness, Andy R.
AU - St Pourcain, Beate
AU - Davey Smith, George
AU - Lewis, Sarah J.
N1 - Funding Information: We would like to thank all of the participants involved in this study as well as the funders and supporting organisations. L. J. H., G. H., G. D. S. and S. J. L. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1). S. J. L. is funded by the HEFCE and by a programme grant awarded by CRUK (ICEP, Principle Investigators: Martin and Relton), G. H. is funded by the Wellcome Trust (208806/Z/17/Z). Funding support for the nsCL/P ICC study was provided by several previous grants from the National Institute of Dental and Craniofacial Research (NIDCR). Funding for individual investigators include: R21-DE-013707 and R01-DE-014581 (Beaty); R37-DE-08559 and P50-DE-016215 (Murray, Marazita) and the Iowa Comprehensive Program to Investigate Craniofacial and Dental Anomalies (Murray); R01-DE-09886 (Marazita), R01-DE-012472 (Marazita), R01-DE-014677 (Marazita), R01-DE-016148 (Marazita), R21-DE016930 (Marazita); R01-DE-013939 (Scott). Parts of this study were supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Wilcox, Lie) and additional recruitment was supported by the Smile Train Foundation for recruitment in China (Jabs, Beaty, Shi) and a grant from the Korean government (Jee). The genome-wide association study, also known 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 U01-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 (U01-HG-004446) and by the National Center for Biotechnology Information (NCBI). The Bonn nsCL/P GWAS was supported by the Deutsche Research Foundation (grant FOR 423, and individual grants MA 2546/3-1 to E.M, and LU 1944/3-1 to K.U.L. Genotyping for the OC/OPC GWAS data set was performed at the Center for Inherited Disease Research (CIDR), funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780-0. Genotyping for shared controls with the Lung OncoArray initiative was funded through the grant X01HG007492-0. The University of Pittsburgh head and neck cancer case–control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-300 0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19 CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission's 5th Framework Program (QLK1-306 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to SB, and Fondazione Veronesi to SB. The IARC Central Europe study was supported by European Commission's INCO-COPERNICUS Program (IC15-CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by: grant S06 96 202489 05F02 from Europe against Cancer; Grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; UICC Yamagiwa-Yoshida Memorial International Cancer Study; National Cancer Institute of Canada; Italian Association for Research on Cancer; and the Pan American Health Organization. The coordination of EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer. UK Biobank received ethical approval from the Research Ethics Committee (11/NW/0383). This study was approved as part of application 15825 (PI: Dr Philip Haycock). The funders did not participate in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: We would like to thank all of the participants involved in this study as well as the funders and supporting organisations. L. J. H., G. H., G. D. S. and S. J. L. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1). S. J. L. is funded by the HEFCE and by a programme grant awarded by CRUK (ICEP, Principle Investigators: Martin and Relton), G. H. is funded by the Wellcome Trust (208806/Z/17/Z). Funding support for the nsCL/P ICC study was provided by several previous grants from the National Institute of Dental and Craniofacial Research (NIDCR). Funding for individual investigators include: R21‐DE‐013707 and R01‐DE‐014581 (Beaty); R37‐DE‐08559 and P50‐DE‐016215 (Murray, Marazita) and the Iowa Comprehensive Program to Investigate Craniofacial and Dental Anomalies (Murray); R01‐DE‐09886 (Marazita), R01‐DE‐012472 (Marazita), R01‐DE‐014677 (Marazita), R01‐DE‐016148 (Marazita), R21‐DE016930 (Marazita); R01‐DE‐013939 (Scott). Parts of this study were supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Wilcox, Lie) and additional recruitment was supported by the Smile Train Foundation for recruitment in China (Jabs, Beaty, Shi) and a grant from the Korean government (Jee). The genome‐wide association study, also known 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 U01‐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 (U01‐HG‐004446) and by the National Center for Biotechnology Information (NCBI). The Bonn nsCL/P GWAS was supported by the Deutsche Research Foundation (grant FOR 423, and individual grants MA 2546/3‐1 to E.M, and LU 1944/3‐1 to K.U.L. Genotyping for the OC/OPC GWAS data set was performed at the Center for Inherited Disease Research (CIDR), funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780‐0. Genotyping for shared controls with the Lung OncoArray initiative was funded through the grant X01HG007492‐0. The University of Pittsburgh head and neck cancer case–control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01‐CA90731). The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP‐PG‐300 0707‐10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19 CA148127) and the Cancer Care Ontario Research Chair. The alcohol‐related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission's 5th Framework Program (QLK1‐306 2001‐00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to SB, and Fondazione Veronesi to SB. The IARC Central Europe study was supported by European Commission's INCO‐COPERNICUS Program (IC15‐CT98‐0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by: grant S06 96 202489 05F02 from Europe against Cancer; Grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; UICC Yamagiwa‐Yoshida Memorial International Cancer Study; National Cancer Institute of Canada; Italian Association for Research on Cancer; and the Pan American Health Organization. The coordination of EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer. UK Biobank received ethical approval from the Research Ethics Committee (11/NW/0383). This study was approved as part of application 15825 (PI: Dr Philip Haycock). The funders did not participate in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Publisher Copyright: © 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC
PY - 2020/11
Y1 - 2020/11
N2 - It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p =.000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p =.55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
AB - It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p =.000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p =.55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
KW - Mendelian randomization
KW - birth defects
KW - genetic epidemiology
KW - oral cancers
KW - orofacial clefts
KW - polygenic risk scores
UR - http://www.scopus.com/inward/record.url?scp=85088401995&partnerID=8YFLogxK
U2 - 10.1002/gepi.22343
DO - 10.1002/gepi.22343
M3 - Article
C2 - 32710482
AN - SCOPUS:85088401995
VL - 44
SP - 924
EP - 933
JO - Genetic Epidemiology
JF - Genetic Epidemiology
SN - 0741-0395
IS - 8
ER -