Nina Ishorst1,2, Paola Francheschelli3, Anne C Böhmer1,2, Mohammad Faisal J Khan3, Stefanie Heilmann-Heimbach1,2, Nadine Fricker1,2, Julian Little4, Regine P M Steegers-Theunissen5, Borut Peterlin6, Stefanie Nowak2, Markus Martini7, Teresa Kruse8, Anton Dunsche9, Thomas Kreusch10, Lina Gölz11, Khalid Aldhorae12, Esam Halboub13, Heiko Reutter2,14, Peter Mossey15, Markus M Nöthen1,2, Michele Rubini3, Kerstin U Ludwig1,2, Michael Knapp16, Elisabeth Mangold2. 1. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. 2. Institute of Human Genetics, University of Bonn, Bonn, Germany. 3. Department of Biomedical and Specialty Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy. 4. School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada. 5. Department of Obstetrics and Gynaecology, Department of Pediatrics, Division Neonatology Erasmus MC, University Medical Center, Rotterdam, The Netherlands. 6. Department of Obstetrics & Gynecology, Clinical Institute of Medical Genetics, University Medical Center Ljubljana, Ljubljana, Slovenia. 7. Department of Oral and Maxillo-Facial-Plastic Surgery, University of Bonn, Bonn, Germany. 8. Department of Orthodontics, University of Cologne, Cologne, Germany. 9. Department of Oral and Maxillo-Facial Surgery, Clinics Karlsruhe, Karlsruhe, Germany. 10. Department of Oral and Maxillofacial Surgery, Head and Neck Centre, Asklepios Klinik Nord-Heidberg, Hamburg, Germany. 11. Department of Orthodontics, University of Bonn, Bonn, Germany. 12. Orthodontic Department, College of Dentistry, Thamar University, Thamar, Yemen. 13. Department of Maxillofacial Surgery and Diagnostic Sciences, Devision of Oral Medicine and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia. 14. Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany. 15. Dental Hospital, University of Dundee, Dundee, United Kingdom. 16. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
Abstract
BACKGROUND: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci. METHODS: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed. RESULTS: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4 ; rs6809420: PMetaAll = 2.80 × 10-4 ). CONCLUSION: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.
BACKGROUND:Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci. METHODS: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed. RESULTS: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4 ; rs6809420: PMetaAll = 2.80 × 10-4 ). CONCLUSION: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.
Keywords:
association study; candidate loci; common variants; congenital malformation; imputed genome-wide association study; nonsyndromic cleft palate only
Authors: Katiúcia Batista Silva Paiva; Clara Soeiro Maas; Pâmella Monique Dos Santos; José Mauro Granjeiro; Ariadne Letra Journal: Front Cell Dev Biol Date: 2019-12-13
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