Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate
Kelsey Robinson,
Trenell J. Mosley,
Kenneth S. Rivera-González,
Christopher R. Jabbarpour,
Sarah W. Curtis,
Wasiu Lanre Adeyemo,
Terri H. Beaty,
Azeez Butali,
Carmen J. Buxó,
David J. Cutler,
Michael P. Epstein,
Lord J.J. Gowans,
Jacqueline T. Hecht,
Jeffrey C. Murray,
Gary M. Shaw,
Lina Moreno Uribe,
Seth M. Weinberg,
Harrison Brand,
Mary L. Marazita,
Robert J. Lipinski,
Elizabeth J. Leslie
Affiliations
Kelsey Robinson
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Trenell J. Mosley
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Kenneth S. Rivera-González
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
Christopher R. Jabbarpour
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
Sarah W. Curtis
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Wasiu Lanre Adeyemo
Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos 101017, Nigeria
Terri H. Beaty
Department of Epidemiology, Johns Hopkins University, Baltimore, MD 21218, USA
Azeez Butali
Department of Oral Biology, Radiology, and Medicine, University of Iowa, Iowa City, IA 52242, USA
Carmen J. Buxó
School of Dental Medicine, University of Puerto Rico, San Juan, PR 00925, USA
David J. Cutler
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Michael P. Epstein
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Lord J.J. Gowans
Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
Jacqueline T. Hecht
Department of Pediatrics, McGovern Medical School University of Texas Health at Houston, Houston, TX 77030, USA
Jeffrey C. Murray
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
Gary M. Shaw
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
Lina Moreno Uribe
Department of Orthodontics & The Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA 52242, USA
Seth M. Weinberg
Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, and Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
Harrison Brand
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Mary L. Marazita
Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, and Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
Robert J. Lipinski
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
Elizabeth J. Leslie
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA; Corresponding author
Summary: Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10−8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10−6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.
