TY - JOUR T1 - A novel method for systematic genetic analysis and visualization of phenotypic heterogeneity applied to orofacial clefts JF - bioRxiv DO - 10.1101/332270 SP - 332270 AU - Jenna C. Carlson AU - Deepti Anand AU - Carmen J. Buxo AU - Kaare Christensen AU - Frederic Deleyiannis AU - Jacqueline T. Hecht AU - Lina M. Moreno AU - Ieda M. Orioli AU - Carmencita Padilla AU - John R. Shaffer AU - Alexandre R. Vieira AU - George L. Wehby AU - Seth M. Weinberg AU - Jeffrey C. Murray AU - Terri H. Beaty AU - Irfan Saadi AU - Salil A. Lachke AU - Mary L. Marazita AU - Eleanor Feingold AU - Elizabeth J. Leslie Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/05/28/332270.abstract N2 - 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 variously 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 the study of complex traits. We applied this technique to create a “cleft map” of the association of 30 genetic loci with these three OFC subtypes. In addition to new associations with OFCs, we found loci with subtype-specific effects (e.g., GRHL3 (CP), WNT5A (CLP), and COL8A1 (CL)), as well as loci associated with two or all three subtypes. Within the IRF6 and 8q24 loci, of which are both strongly associated with CL/P (CL with or without CP), we found multiple independent signals, including some with subtype-specific effects. 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 gene 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.Author Summary Orofacial clefts (OFCs), which include cleft lip and cleft palate, are the most common craniofacial birth defects in humans. Like many complex traits, OFCs exhibit striking phenotypic heterogeneity with three distinct anatomical subtypes (cleft lip, cleft lip and palate, and cleft palate). Despite the rapid pace of discovery of genetic variants influencing risk for OFC, how these variants influence these different OFC subtypes remains unknown. We developed a quantitative framework to interpret the evidence for subtype-specific or shared genetic effects for complex traits and applied it to 30 loci associated with OFCs. We found evidence for both subtype-specific genetic effects, as well as shared effects between two or all three subtypes, reflecting the complexity of genetic influences on risk to OFC. The results of this study will improve our ability to connect specific genetic variants to human phenotypes, understand the function of these genes and variants on craniofacial development, and pave the way for more predictive risk models. ER -