Francesca Cura1, Anne C Böhmer2,3, Johanna Klamt2,3, Hannah Schünke2,3, Luca Scapoli1, Marcella Martinelli1, Francesco Carinci4, Markus M Nöthen2,3, Michael Knapp5, Kerstin U Ludwig2,3, Elisabeth Mangold2. 1. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. 2. Institute of Human Genetics, University of Bonn, Bonn, Germany. 3. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. 4. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy. 5. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
Abstract
BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. METHODS: At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. RESULTS: Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations. CONCLUSION: Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment.
BACKGROUND:Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. METHODS: At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. RESULTS: Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations. CONCLUSION: Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment.
Authors: Enrique Lin-Shiao; Yemin Lan; Julia Welzenbach; Katherine A Alexander; Zhen Zhang; Michael Knapp; Elisabeth Mangold; Morgan Sammons; Kerstin U Ludwig; Shelley L Berger Journal: Sci Adv Date: 2019-05-01 Impact factor: 14.136