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

doi:10.1016/j.xhgg.2021.100038

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

HGG Adv. 2021 Jun 8;2(3):100038. doi: 10.1016/j.xhgg.2021.100038. eCollection 2021 Jul 8.

Authors

Julia Welzenbach¹, Nigel L Hammond², Miloš Nikolić³, Frederic Thieme¹, Nina Ishorst¹, Elizabeth J Leslie⁴, Seth M Weinberg^{5

6}, Terri H Beaty⁷, Mary L Marazita^{5

6

8}, Elisabeth Mangold¹, Michael Knapp⁹, Justin Cotney^{10

11}, Alvaro Rada-Iglesias^{3

12

13}, Michael J Dixon², Kerstin U Ludwig¹

Affiliations

¹ Institute of Human Genetics, University Hospital Bonn, Medical Faculty, Venusberg-Campus 1, 53127 Bonn, Germany.
² Faculty of Biology, Medicine, and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, UK.
³ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁴ Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.
⁵ Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Psychiatry and Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁹ Institute of Medical Biometry, Informatics, and Epidemiology, University Hospital Bonn, Bonn, Germany.
¹⁰ Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
¹¹ Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA.
¹² Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹³ Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria, Cantabria, Spain.

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.

Keywords: GWAS; chromatin mark; cleft; craniofacial development; regulatory effects.

Abstract

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