A Systematic Genetic Analysis and Visualization of Phenotypic Heterogeneity Among Orofacial Cleft GWAS Signals

Overview

Journal Genet Epidemiol

Specialties Genetics
Public Health

Date 2019 Jun 8

PMID 31172578

Citations 25

Authors

Jenna C Carlson

Deepti Anand

Azeez Butali

Carmen J Buxo

Kaare Christensen

Frederic Deleyiannis

Jacqueline T Hecht

Lina M Moreno

Ieda M Orioli

Carmencita Padilla

John R Shaffer

Alexandre R Vieira

George L Wehby

Seth M Weinberg

Jeffrey C Murray

Terri H Beaty

Irfan Saadi

Salil A Lachke

Mary L Marazita

Eleanor Feingold

Elizabeth J Leslie

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.

Caetano da Silva C, Macias Trevino C, Mitchell J, Murali H, Tsimbal C, Dalessandro E Commun Biol. 2024; 7(1):1040.

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Functional analysis of gene variants and isoforms in orofacial cleft pathogenesis.

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Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes.

Curtis S, Carlson J, Beaty T, Murray J, Weinberg S, Marazita M Hum Genet. 2023; 142(10):1531-1541.

PMID: 37676273 DOI: 10.1007/s00439-023-02596-4.

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting.

Diaz Perez K, Curtis S, Sanchis-Juan A, Zhao X, Head T, Ho S Genet Med. 2023; 25(10):100918.

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Rare genetic variants in modify orofacial cleft phenotypes.

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PMID: 37034635 PMC: 10081436. DOI: 10.1101/2023.03.24.23287714.

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