A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals

Details

• Alternative Title:
  Genet Epidemiol
• Personal Author:
  Carlson, Jenna C. ; Anand, Deepti ; Butali, Azeez ; Buxo, Carmen J. ; Christensen, Kaare ; Deleyiannis, Frederic ; Hecht, Jacqueline T. ; Moreno, Lina M. ; Orioli, Ieda M. ; Padilla, Carmencita ; Shaffer, John R. ; Vieira, Alexandre R. ; Wehby, George L. ; Weinberg, Seth M. ; Murray, Jeffrey C. ; Beaty, Terri H. ; Saadi, Irfan ; Lachke, Salil A. ; Marazita, Mary L. ; Feingold, Eleanor ; Leslie, Elizabeth J.
• Description:
  Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.
• Subjects:
  Brain Cleft Lip Cleft Palate Genetic Loci Genetic Markers Genetic Testing Genome-Wide Association Study Humans Phenotype Transcriptome
• Keywords:
  Birth Defects Buprenorphine Genome-wide Association Studies Methadone Mortality Naltrexone Orofacial Clefts Subtypes Treatment
• Source:
  Genet Epidemiol. 43(6):704-716
• Pubmed ID:
  31172578
• Pubmed Central ID:
  PMC6687557
• Document Type:
  Journal Article
• Funding:
  R01 DE014667/DE/NIDCR NIH HHSUnited States/ ; U54 GM133807/GM/NIGMS NIH HHSUnited States/ ; U01 DE018993/DE/NIDCR NIH HHSUnited States/ ; U54 MD007587/MD/NIMHD NIH HHSUnited States/ ; UL1 TR003167/TR/NCATS NIH HHSUnited States/ ; S21 MD001830/MD/NIMHD NIH HHSUnited States/ ; HHSN268201200008C/HL/NHLBI NIH HHSUnited States/ ; R01 DE014581/DE/NIDCR NIH HHSUnited States/ ; R01 DE011948/DE/NIDCR NIH HHSUnited States/ ; U54 HD090216/HD/NICHD NIH HHSUnited States/ ; R00 DE025060/DE/NIDCR NIH HHSUnited States/ ; R37 DE008559/DE/NIDCR NIH HHSUnited States/ ; R01 DE011931/DE/NIDCR NIH HHSUnited States/ ; R00 DE024571/DE/NIDCR NIH HHSUnited States/ ; R01 DE016148/DE/NIDCR NIH HHSUnited States/ ; R03 DE024776/DE/NIDCR NIH HHSUnited States/ ; R21 DE016930/DE/NIDCR NIH HHSUnited States/ ; R00 DE022378/DE/NIDCR NIH HHSUnited States/ ; X01-HG007485 [MLM/NH/NIH HHSUnited States/ ; HHSN268201200008I/HL/NHLBI NIH HHSUnited States/ ; R01 DE009886/DE/NIDCR NIH HHSUnited States/ ; R01 DE026172/DE/NIDCR NIH HHSUnited States/ ; R01 DD000295/DD/NCBDD CDC HHSUnited States/ ; R01-DE012472 [MLM]/NH/NIH HHSUnited States/
• Volume:
  43
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:653d1f5feccfc2fe77bf00b4d919b13779f081f00bde7f8da481ec3bf09a429544eff59254ae618082a09ea54123e3012a19a9e2e58b5a2fa3b2d27020c61117
• Download URL:
  https://stacks.cdc.gov/view/cdc/80600/cdc_80600_DS1.pdf
• File Type:
  [PDF - 691.75 KB ]