Journal article
Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci
American journal of human genetics, Vol.96(3), pp.397-411
03/05/2015
DOI: 10.1016/j.ajhg.2015.01.004
PMCID: PMC4375420
PMID: 25704602
Abstract
Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans.
Details
- Title: Subtitle
- Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci
- Creators
- Elizabeth J Leslie - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: ejl40@pitt.eduMargaret A Taub - Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USAHuan Liu - Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA; State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 430072 Wuhan, ChinaKaryn Meltz Steinberg - The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USADaniel C Koboldt - The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USAQunyuan Zhang - Department of Statistical Genetics, Washington University School of Medicine, St. Louis, MO 63108, USAJenna C Carlson - Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USAJacqueline B Hetmanski - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USAHang Wang - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USADavid E Larson - The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USARobert S Fulton - The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USAYoussef A Kousa - Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USAWalid D Fakhouri - Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77030, USAAli Naji - Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77030, USAIngo Ruczinski - Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USAFerdouse Begum - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USAMargaret M Parker - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USATamara Busch - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAJennifer Standley - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAJennifer Rigdon - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAJacqueline T Hecht - Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USAAlan F Scott - Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USAGeorge L Wehby - Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52242, USAKaare Christensen - Department of Epidemiology, Institute of Public Health, University of Southern Denmark, 5230 Odense, DenmarkAndrew E Czeizel - Foundation for the Community Control of Hereditary Diseases, Budapest 1148, HungaryFrederic W-B Deleyiannis - Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USABrian C Schutte - Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USARichard K Wilson - The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USARobert A Cornell - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAAndrew C Lidral - Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USAGeorge M Weinstock - The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06117, USATerri H Beaty - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USAMary L Marazita - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Human Genetics, Graduate School of Public Health, and Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: marazita@pitt.eduJeffrey C Murray - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.96(3), pp.397-411
- DOI
- 10.1016/j.ajhg.2015.01.004
- PMID
- 25704602
- PMCID
- PMC4375420
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- United States
- Grant note
- T32 GM008629 / NIGMS NIH HHS DE018993 / NIDCR NIH HHS DE014581 / NIDCR NIH HHS DE008559 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS HD073107 / NICHD NIH HHS HG005925 / NHGRI NIH HHS R01 DE023575 / NIDCR NIH HHS R01 DE014581 / NIDCR NIH HHS DE022696 / NIDCR NIH HHS U01 DE020057 / NIDCR NIH HHS U01 HG005925 / NHGRI NIH HHS R01 DE009886 / NIDCR NIH HHS DE011931 / NIDCR NIH HHS F31 DE022696 / NIDCR NIH HHS T15 LM007059 / NLM NIH HHS R21 DE016930 / NIDCR NIH HHS LM007059 / NLM NIH HHS U01 DE018993 / NIDCR NIH HHS DE016930 / NIDCR NIH HHS GM008629 / NIGMS NIH HHS R37 DE008559 / NIDCR NIH HHS DE009886 / NIDCR NIH HHS R01 DE011931 / NIDCR NIH HHS
- Language
- English
- Date published
- 03/05/2015
- Academic Unit
- Preventive and Community Dentistry; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984025341202771
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