Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

Details

• Alternative Title:
  Hum Genet
• Personal Author:
  Leslie, Elizabeth J. ; Carlson, Jenna C. ; Shaffer, John R. ; Butali, Azeez ; Buxó, Carmen J. ; Castilla, Eduardo E. ; Christensen, Kaare ; Deleyiannis, Fred W.-B. ; Field, L. Leigh ; Hecht, Jacqueline T. ; Moreno, Lina ; Orioli, Ieda M. ; Padilla, Carmencita ; Vieira, Alexandre R. ; Wehby, George L. ; Feingold, Eleanor ; Weinberg, Seth M. ; Murray, Jeffrey C. ; Beaty, Terri H. ; Marazita, Mary L.
• Description:
  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 × 10|). 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 × 10|). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.
• Keywords:
  Chromosome Mapping Cleft Lip Cleft Palate Forkhead Transcription Factors Genome-Wide Association Study Humans Polymorphism, Single Nucleotide Transcription Factors Tumor Suppressor Proteins
• Source:
  Hum Genet. 136(3):275-286
• Pubmed ID:
  28054174
• Pubmed Central ID:
  PMC5317097
• Document Type:
  Journal Article
• Funding:
  R01 DE014667/DE/NIDCR NIH HHSUnited States/ ; U54 MD007587/MD/NIMHD NIH HHSUnited States/ ; K99 DE025060/DE/NIDCR NIH HHSUnited States/ ; HHSN268201200008C/HL/NHLBI NIH HHSUnited States/ ; R01 DE014581/DE/NIDCR NIH HHSUnited States/ ; R01 DE011948/DE/NIDCR NIH HHSUnited States/ ; U01 DE024425/DE/NIDCR NIH HHSUnited States/ ; R00 DE025060/DE/NIDCR NIH HHSUnited States/ ; R21 DE016930/DE/NIDCR NIH HHSUnited States/ ; K99 DE024571/DE/NIDCR NIH HHSUnited States/ ; R01 DD000295/DD/NCBDD CDC HHSUnited States/ ; R37 DE008559/DE/NIDCR NIH HHSUnited States/ ; R01 DE011931/DE/NIDCR NIH HHSUnited States/ ; R25 MD007607/MD/NIMHD NIH HHSUnited States/ ; U01 DE018993/DE/NIDCR NIH HHSUnited States/ ; R00 DE024571/DE/NIDCR NIH HHSUnited States/ ; R01 DE016148/DE/NIDCR NIH HHSUnited States/ ; HHSN268201200008I/HL/NHLBI NIH HHSUnited States/ ; R01 DE009886/DE/NIDCR NIH HHSUnited States/
• Volume:
  136
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:cc572ad8090b16c1a926d871b04854832c32306033754ff0468c3a5188376dba
• Download URL:
  https://stacks.cdc.gov/view/cdc/44305/cdc_44305_DS1.pdf
• File Type:
  [PDF - 1.20 MB ]