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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
  • Published Date:
    Jan 04 2017
  • Source:
    Hum Genet. 136(3):275-286.


Public Access Version Available on: March 01, 2018 information icon
Please check back on the date listed above.
Details:
  • Pubmed ID:
    28054174
  • Pubmed Central ID:
    PMC5317097
  • 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(-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 × 10(-9)). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

  • Document Type:
  • Funding:
    R37 DE008559/DE/NIDCR NIH HHS/United States
    R01 DE011931/DE/NIDCR NIH HHS/United States
    R01 DE014667/DE/NIDCR NIH HHS/United States
    R25 MD007607/MD/NIMHD NIH HHS/United States
    U01 DE018993/DE/NIDCR NIH HHS/United States
    U54 MD007587/MD/NIMHD NIH HHS/United States
    K99 DE025060/DE/NIDCR NIH HHS/United States
    S21 MD001830/MD/NIMHD NIH HHS/United States
    HHSN268201200008C/HL/NHLBI NIH HHS/United States
    R01 DE014581/DE/NIDCR NIH HHS/United States
    R01 DE016148/DE/NIDCR NIH HHS/United States
    R01 DE011948/DE/NIDCR NIH HHS/United States
    U01 DE024425/DE/NIDCR NIH HHS/United States
    R21 DE016930/DE/NIDCR NIH HHS/United States
    HHSN268201200008I/HL/NHLBI NIH HHS/United States
    R01 DE009886/DE/NIDCR NIH HHS/United States
    K99 DE024571/DE/NIDCR NIH HHS/United States
    R01 DD000295/DD/NCBDD CDC HHS/United States
  • Supporting Files:
    No Additional Files
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