A novel method for systematic genetic analysis and visualization of phenotypic heterogeneity applied to orofacial clefts

Abstract Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies may focus on the trait as a whole or on individual subgroups. 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. It is more challenging, however, to dissect the genetic architecture and describe how a given 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 promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed 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.