Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate

Details

• Alternative Title:
  Am J Med Genet A
• Personal Author:
  Leslie, Elizabeth J. ; Carlson, Jenna C. ; Shaffer, John R. ; Buxó, Carmen J. ; Castilla, Eduardo E. ; Christensen, Kaare ; Deleyiannis, Frederic 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. ; Marazita, Mary L.
• Description:
  Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The "missing" heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P.
• Subjects:
  Alleles Article Association Basic Helix-Loop-Helix Transcription Factors Brain Burden Test Cleft Lip Cleft Palate DNA Repair Enzymes Exome Gene Frequency Genetic Predisposition To Disease Genome-Wide Association Study Genotype Glycoproteins Humans Intercellular Signaling Peptides And Proteins Membrane Proteins Orofacial Cleft Polymorphism, Single Nucleotide Rare Variant Repressor Proteins Risk Factors White People

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• Source:
  Am J Med Genet A. 173(6):1531-1538
• Pubmed ID:
  28425186
• Pubmed Central ID:
  PMC5444956
• Document Type:
  Journal Article
• Funding:
  R01 DE014667/DE/NIDCR NIH HHSUnited States/ ; R25 MD007607/MD/NIMHD NIH HHSUnited States/ ; U54 MD007587/MD/NIMHD NIH HHSUnited States/ ; K99 DE025060/DE/NIDCR NIH HHSUnited States/ ; HHSN268201200008C/HL/NHLBI NIH HHSUnited States/ ; R01 DE016148/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/ ; HHSN268201200008I/HL/NHLBI NIH HHSUnited States/ ; R01 DE009886/DE/NIDCR NIH HHSUnited States/
• Volume:
  173
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:a5c373cd1d564d311487c135561515e3999628c1970c1db322021d53d379736b
• Download URL:
  https://stacks.cdc.gov/view/cdc/45908/cdc_45908_DS1.pdf
• File Type:
  [PDF - 208.83 KB ]