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

Published Date:

June 06 2019

Source:

Genet Epidemiol. 43(6):704-716

Language:

English

Public Access Version Available on: September 01, 2020, 12:00 AM

Please check back on the date listed above.

Details:

Alternative Title:

Genet Epidemiol

Personal Author:

Carlson, Jenna C. ; Anand, Deepti ; Butali, Azeez ; Buxo, Carmen J. ; Christensen, Kaare ; ... More ▼

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.

Subject:

[+]

Pubmed ID:

31172578

Pubmed Central ID:

PMC6687557

Document Type:

Journal Article

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 ; U01 DE018993/DE/NIDCR NIH HHS/United States ; U54 MD007587/MD/NIMHD NIH HHS/United States ; ... More ▼

Collection(s):

CDC Public Access

Main Document Checksum:

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Supporting Files:

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