期刊
GENETIC EPIDEMIOLOGY
卷 46, 期 3-4, 页码 182-198出版社
WILEY
DOI: 10.1002/gepi.22447
关键词
comparison of genetic etiology; genome-wide association; multiethnic study; subtypes of orofacial clefts
资金
- Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila, grants through FAPERJ
- Research Institute of the Children's Hospital of Colorado
- NIH National Institute of Dental and Craniofacial Research [R01-DE-016148, U01-DE024425, R37-DE-008559, R01-DE009886, R21-DE016930, R01-DE014667, R01-DE012472, R01-DE011931, U01-DD000295, R00-DE025060, R01-DE028342, R01-DE28300, K99/R00DE024571]
- National Institute on Minority Health and Health Disparities [S21MD001830]
- NIH National Institute of General Medical Sciences [U54GM133807]
- NIH National Human Genome Research Institute [X01-HG007485]
Nonsyndromic orofacial clefts (OFCs) are common craniofacial birth defects with phenotypic and genetic heterogeneity. This study conducted a genome-wide association study on different types of cases and controls from the Pittsburgh Orofacial Cleft study. It identified novel significant associations and confirmed OFC loci, as well as genetic differences between CL and CLP.
Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p <= 1.0E-05) within previously confirmed OFC loci-PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster-were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.
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