Integrative approaches generate insights into the architecture of non-syndromic cleft lip with or without cleft palate

• Type of Material: Article
• Authors: Julia Welzenbach, University Hospital Bonn; Nigel L. Hammond, University of Manchester; Milos Nikolic, University of Cologne; Frederic Thieme, University Hospital Bonn; Nina Ishorst, University Hospital Bonn; Elizabeth Leslie, Emory University; Seth M. Weinberg, University of Pittsburgh; Terri H. Beaty, Johns Hopkins University; Mary L. Marazita, University of Pittsburgh; Elisabeth Mangold, University Hospital Bonn; Michael Knapp, University Hospital Bonn; Justin Cotney, University of Connecticut; Alvaro Rada-Iglesias, University of Cologne; Michael J. Dixon, University of Manchester; Kerstin U. Ludwig, University Hospital Bonn
• Language: English
• Date: 2021-07-08
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.xhgg.2021.100038
• Title of Journal or Parent Work: Human Genetics and Genomics Advances
• Volume: 2
• Issue: 3
• Grant/Funding Information: This work was supported by the German Research Foundation (DFG; LU 1944/3-1, to K.U.L.).
• Keywords: craniofacial development; regulatory effects; GWAS; cleft; chromatin mark
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common congenital facial malformation with a multifactorial etiology. Genome-wide association studies (GWASs) have identified multiple genetic risk loci. However, functional interpretation of these loci is hampered by the underrepresentation in public resources of systematic functional maps representative of human embryonic facial development. To generate novel insights into the etiology of nsCL/P, we leveraged published GWAS data on nsCL/P as well as available chromatin modification and expression data on mid-facial development. Our analyses identified five novel risk loci, prioritized candidate target genes within associated regions, and highlighted distinct pathways. Furthermore, the results suggest the presence of distinct regulatory effects of nsCL/P risk variants throughout mid-facial development and shed light on its regulatory architecture. Our integrated data provide a platform to advance hypothesis-driven molecular investigations of nsCL/P and other human facial defects.