Integrative approaches generate insights into the architecture of non-syndromic cleft lip with or without cleft palate
Julia Welzenbach,
Nigel L. Hammond,
Miloš Nikolić,
Frederic Thieme,
Nina Ishorst,
Elizabeth J. Leslie,
Seth M. Weinberg,
Terri H. Beaty,
Mary L. Marazita,
Elisabeth Mangold,
Michael Knapp,
Justin Cotney,
Alvaro Rada-Iglesias,
Michael J. Dixon,
Kerstin U. Ludwig
Affiliations
Julia Welzenbach
Institute of Human Genetics, University Hospital Bonn, Medical Faculty, Venusberg-Campus 1, 53127 Bonn, Germany
Nigel L. Hammond
Faculty of Biology, Medicine, and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, UK
Miloš Nikolić
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Frederic Thieme
Institute of Human Genetics, University Hospital Bonn, Medical Faculty, Venusberg-Campus 1, 53127 Bonn, Germany
Nina Ishorst
Institute of Human Genetics, University Hospital Bonn, Medical Faculty, Venusberg-Campus 1, 53127 Bonn, Germany
Elizabeth J. Leslie
Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA
Seth M. Weinberg
Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
Terri H. Beaty
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
Mary L. Marazita
Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry and Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
Elisabeth Mangold
Institute of Human Genetics, University Hospital Bonn, Medical Faculty, Venusberg-Campus 1, 53127 Bonn, Germany
Michael Knapp
Institute of Medical Biometry, Informatics, and Epidemiology, University Hospital Bonn, Bonn, Germany
Justin Cotney
Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA; Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
Alvaro Rada-Iglesias
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria, Cantabria, Spain
Michael J. Dixon
Faculty of Biology, Medicine, and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, UK
Kerstin U. Ludwig
Institute of Human Genetics, University Hospital Bonn, Medical Faculty, Venusberg-Campus 1, 53127 Bonn, Germany; Corresponding author
Summary: 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.
