title: Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only.
abstract: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Böhmer
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.affiliation: Center for Molecular Medicine Cologne.|Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
authors.forename: Miloš
authors.initials: M
authors.lastname: Nikolic
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Ishorst
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Niki
authors.initials: N
authors.lastname: Wyatt
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Nigel L
authors.initials: NL
authors.lastname: Hammond
authors.affiliation: Department of Orthodontics, University of Bonn, Bonn 53111, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Gölz
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Thieme
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Barth
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Schuenke
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Klamt
authors.affiliation: Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin 14195, Germany.|Institute for Medical and Human Genetics.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin 13353, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.affiliation: Orthodontic Department, College of Dentistry, Thamar University, Thamar, Yemen.
authors.forename: Khalid
authors.initials: K
authors.lastname: Aldhorae
authors.affiliation: Tecnologico de Monterrey, School of Medicine, and Universidad Autonoma de Nuevo Leon, Centro de Investigación y Desarrollo en Ciencias de la Salud, Monterrey 64460, Mexico.
authors.forename: Augusto
authors.initials: A
authors.lastname: Rojas-Martinez
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Center for Molecular Medicine Cologne.|Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Rada-Iglesias
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dixon
authors.affiliation: Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Institute of Human Genetics University of Bonn, Bonn 53127, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
mesh_terms: D000818:Animals; D002877:Chromosomes, Human / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D030541:Databases, Genetic; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide