Beaty, T. | Search bioRxiv

bioRxiv2020

Coding de novo mutations identified by WGS reveal novel orofacial cleft genes

While de novo mutations (DNMs) are known to increase risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 case-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

genetics↗

bioRxiv2018

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

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.

genetics↗