Premium
A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals
Author(s) -
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.
Publication year - 2019
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.22214
Subject(s) - genetic architecture , biology , genetic heterogeneity , genetics , phenotype , genome wide association study , quantitative trait locus , locus (genetics) , craniofacial , trait , gene , genetic association , candidate gene , computational biology , genotype , single nucleotide polymorphism , computer science , programming language
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.