Genome Wide Interaction Studies Identify Sex-Specific Risk Alleles for Nonsyndromic Orofacial Clefts

Details

• Alternative Title:
  Genet Epidemiol
• Personal Author:
  Carlson, Jenna C. ; Nidey, Nichole L. ; Butali, Azeez ; Buxo, Carmen J. ; Christensen, Kaare ; Deleyiannis, Frederic W-D ; Hecht, Jacqueline T. ; Field, L. Leigh ; Moreno-Uribe, Lina M. ; Orioli, Ieda M. ; Poletta, Fernando A. ; Padilla, Carmencita ; Vieira, Alexandre R. ; Weinberg, Seth M. ; Wehby, George L. ; Feingold, Eleanor ; Murray, Jeffrey C. ; Marazita, Mary L. ; Leslie, Elizabeth J. ; Carlson, Jenna C. ; Nidey, Nichole L. ; Butali, Azeez ; Buxo, Carmen J. ; Christensen, Kaare ; Deleyiannis, Frederic W-D ; Hecht, Jacqueline T. ; Field, L. Leigh ; Moreno-Uribe, Lina M. ; Orioli, Ieda M. ; Poletta, Fernando A. ; Padilla, Carmencita ; Vieira, Alexandre R. ; Weinberg, Seth M. ; Wehby, George L. ; Feingold, Eleanor ; Murray, Jeffrey C. ; Marazita, Mary L. ; Leslie, Elizabeth J.
• Description:
  Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 | ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 | ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 | ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.
• Subjects:
  Alleles Article Brain Case-Control Studies Cleft Lip Cleft Palate Epistasis, Genetic Female Gene Frequency Genetic Loci Genetic Predisposition To Disease Genetic Risk Genome-Wide Association Study Humans Male Models, Genetic Oral Facial Cleft Polymorphism, Single Nucleotide Risk Factors Sex Characteristics

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• Source:
  Genet Epidemiol. 42(7):664-672 ; Genet Epidemiol. 42(7):664-672
• Pubmed ID:
  30277614
• Pubmed Central ID:
  PMC6185762
• Document Type:
  Journal Article
• Funding:
  DE012472/NH/NIH HHS/United States ; U54-MD007587/NH/NIH HHS/United States ; R01-DE016148/NH/NIH HHS/United States ; U01-DE024425/NH/NIH HHS/United States ; R37 DE008559/DE/NIDCR NIH HHS/United States ; PICT-2016-3869/Agencia Nacional de Promoción Científica y Tecnológica/International ; R01 DE011931/DE/NIDCR NIH HHS/United States ; R01 DE014667/DE/NIDCR NIH HHS/United States ; R01-DE014667/NH/NIH HHS/United States ; HHSN268201200008I/Johns Hopkins Center for Inherited Disease Research/International ; R01-DE011948/NH/NIH HHS/United States ; K99-DE024571/NH/NIH HHS/United States ; U54 MD007587/MD/NIMHD NIH HHS/United States ; DE011931/NH/NIH HHS/United States ; S21 MD001830/MD/NIMHD NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R00 DE024571/DE/NIDCR NIH HHS/United States ; DE014667/NH/NIH HHS/United States ; R01 DE016148/DE/NIDCR NIH HHS/United States ; R01 DE011948/DE/NIDCR NIH HHS/United States ; DD000295/NH/NIH HHS/United States ; U01 DE024425/DE/NIDCR NIH HHS/United States ; DE008559/NH/NIH HHS/United States ; DE009886/NH/NIH HHS/United States ; R00 DE025060/DE/NIDCR NIH HHS/United States ; R01 DE008559/DE/NIDCR NIH HHS/United States ; R21 DE016930/DE/NIDCR NIH HHS/United States ; MD001830/NH/NIH HHS/United States ; R00-DE025060/NH/NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R01 DE009886/DE/NIDCR NIH HHS/United States ; X01-HG007485/NH/NIH HHS/United States ; DE016930/NH/NIH HHS/United States ; K99 DE024571/DE/NIDCR NIH HHS/United States ; R01 DD000295/DD/NCBDD CDC HHS/United States
• Volume:
  42
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:1ceed89ed0ed7d6429e847532555107f7623593518e849037abf5f57db00b4f4
• Download URL:
  https://stacks.cdc.gov/view/cdc/59724/cdc_59724_DS1.pdf
• File Type:
  [PDF - 269.05 KB ]