title: Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene.
abstract: Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom.
authors.forename: Syeda Tasnim
authors.initials: ST
authors.lastname: Ahmed
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Böhmer
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom.
authors.forename: Nasim Bahram
authors.initials: NB
authors.lastname: Sangani
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom.
authors.forename: Sheryil
authors.initials: S
authors.lastname: Varghese
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Klamt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Schuenke
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Pinar
authors.initials: P
authors.lastname: Gültepe
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Rubini
authors.affiliation: Orthodontic Department, College of Dentistry, Thamar University, Thamar, Yemen.
authors.forename: Khalid Ahmed
authors.initials: KA
authors.lastname: Aldhorae
authors.affiliation: Department of Obstetrics and Gynaecology, ErasmusMC, Rotterdam, Netherlands.|Department of Epidemiology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Regine P
authors.initials: RP
authors.lastname: Steegers-Theunissen
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, and Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
authors.forename: Augusto
authors.initials: A
authors.lastname: Rojas-Martinez
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Section of Phoniatrics and Pedaudiology, University of Ulm, Ulm, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Reiter
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Division of Anatomy, Kyushu Dental University, Kitakyushu, Japan.
authors.forename: Mitsushiro
authors.initials: M
authors.lastname: Nakatomi
authors.affiliation: Orofacial Development and Regeneration, Institute of Oral Biology, Center for Dental Medicine, University of Zurich, Zurich, Switzerland.|Departments of Dentistry and Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Graf
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom.
authors.forename: Heiko
authors.initials: H
authors.lastname: Peters
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002884:Chromosomes, Human, Pair 15; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D044465:White People
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins