期刊
HUMAN GENETICS
卷 136, 期 3, 页码 275-286出版社
SPRINGER
DOI: 10.1007/s00439-016-1754-7
关键词
-
资金
- National Institutes of Health (NIH) [K99-DE025060, X01-HG007485, R01-DE016148, U01-DE024425, R37-DE008559, R01-DE009886, R21-DE016930, R01-DE014667, R01-DE012472, R01-DE011931, R01-DE011948, U01-DD000295, K99-DE024571, R25-MD007607, R01-DE014581, U01-DE018993]
- Johns Hopkins Center for Inherited Disease Research [HHSN268201200008I]
- Robert Wood Johnson Foundation, AMFDP Grant [72429]
- Research Institute of the Children's Hospital of Colorado
- FAPERJ, Brazil
- CNPq, Brazil
- [E-26/102.797/2012]
- [E-26/110.140/2013]
- [481069/2012-7]
- [306396/2013-0]
- [400427/2013-3]
Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 x 10(-8)). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 x 10(-9)). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.
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