Journal article
A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis
Human genetics, Vol.139(8), pp.1077-1090
08/2020
DOI: 10.1007/s00439-020-02157-z
PMCID: PMC7415527
PMID: 32266521
Abstract
Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10
): rs781716 (P = 4.71 × 10
; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10
; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10
; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10
, OR = 0.45; P = 3.31 × 10
, OR = 0.45; P = 1.09 × 10
, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10
, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10
). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.
Details
- Title: Subtitle
- A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis
- Creators
- Cristina M Justice - Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH, Baltimore, MD, USAAraceli Cuellar - Department of Pediatrics, University of California Davis, 4625 2nd Avenue, Research Building II, Sacramento, CA, 95817, USAKrithi Bala - Department of Pediatrics, University of California Davis, 4625 2nd Avenue, Research Building II, Sacramento, CA, 95817, USAJeremy A Sabourin - Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH, Baltimore, MD, USAMichael L Cunningham - Department of Pediatrics, Division of Craniofacial Medicine, Seattle Children's Craniofacial Center, Seattle Children's Research Institute, University of Washington, Seattle, WA, USAKaren Crawford - MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UKJulie M Phipps - Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UKYan Zhou - MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UKDeirdre Cilliers - Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UKJo C Byren - Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UKDavid Johnson - Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSteven A Wall - Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UKJenny E V Morton - Birmingham Craniofacial Unit, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UKPeter Noons - Birmingham Craniofacial Unit, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UKElizabeth Sweeney - Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, England, UKAstrid Weber - Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, England, UKKatie E M Rees - Clinical Genetics Service, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UKLouise C Wilson - Clinical Genetics Service, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UKEmil Simeonov - National Institute of Pediatrics, Sofia Medical University, Sofia, BulgariaRadka Kaneva - Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, Sofia, BulgariaNadezhda Yaneva - National Genetic Laboratory, University Hospital of Obstetrics and Gynecology "Maichin Dom", Medical University of Sofia, Sofia, BulgariaKiril Georgiev - Department of Neurosurgery, University Hospital 'St. Ivan Rilski', Medical University of Sofia, Sofia, BulgariaAssen Bussarsky - Department of Neurosurgery, University Hospital 'St. Ivan Rilski', Medical University of Sofia, Sofia, BulgariaCraig Senders - Department of Otolaryngology, Head and Neck Surgery, University of California Davis, Sacramento, CA, USAMarike Zwienenberg - Department of Neurosurgery, University of California Davis, Sacramento, CA, USAJames Boggan - Department of Neurosurgery, University of California Davis, Sacramento, CA, USATony Roscioli - Neuroscience Research Australia, University of New South Wales, Sydney, AustraliaGianpiero Tamburrini - Section of Neurosurgery, Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, ItalyMarta Barba - Section of Experimental Biology, Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, ItalyKristin Conway - Department of Epidemiology, College of Public Health, The University of Iowa, 145 N Riverside Dr, S416 CPHB, Iowa City, IA, 52242, USAVal C Sheffield - Department of Pediatrics, Division of Medical Genetics, Carver College of Medicine, The University of Iowa, Iowa City, IA, USALawrence Brody - Gene and Environment Interaction Section, NHGRI, Bethesda, NIHMD, USAJames L Mills - Epidemiology Branch, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USADenise Kay - Division of Genetics, NYS Department of Health, Wadsworth CenterAlbany, NY, USARobert J Sicko - Division of Genetics, NYS Department of Health, Wadsworth CenterAlbany, NY, USAPeter H Langlois - Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, TX, USARachel K Tittle - Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USALorenzo D Botto - Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USAMary M Jenkins - National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USAJanine M LaSalle - Department of Medical Microbiology and Immunology, Genome Center, and MIND Institute, University of California Davis, Davis, CA, USAWanda Lattanzi - Section of Experimental Biology, Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, ItalyAndrew O M Wilkie - Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UKAlexander F Wilson - Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH, Baltimore, MD, USAPaul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, 145 N Riverside Dr, S416 CPHB, Iowa City, IA, 52242, USA. paul-romitti@uiowa.eduSimeon A Boyadjiev - Department of Pediatrics, University of California Davis, 4625 2nd Avenue, Research Building II, Sacramento, CA, 95817, USA. sboyd@ucdavis.edu
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.139(8), pp.1077-1090
- DOI
- 10.1007/s00439-020-02157-z
- PMID
- 32266521
- PMCID
- PMC7415527
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Publisher
- Germany
- Grant note
- FOA #DD09-001 / CDC HHS U01 DD001035 / CDC HHS DE018277 / NIDCR NIH HHS Wellcome Trust HHSN27500005 / National Institute of Child Health and Human Development HHSN275201100001C / NICHD NIH HHS NOFO #DD18-001 / CDC HHS U01 DD001223 / CDC HHS PA #96043 / CDC HHS HHSN275201100001G / NICHD NIH HHS U01 DD001035 / NCBDD CDC HHS HHSN268200782096C / NHGRI NIH HHS PA #02081 / CDC HHS FOA #DD13-003 / CDC HHS 102731 / Wellcome Trust U01 DD001227 / NCBDD CDC HHS R01 DE016886 / NIDCR NIH HHS HHSN275201100001I / NICHD NIH HHS CDP 13-003 / HSRD VA 102731/Z/13/Z / Wellcome Trust U01 DD001223 / NCBDD CDC HHS EP-D-18-001 / EPA
- Language
- English
- Date published
- 08/2020
- Academic Unit
- Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Biostatistics; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070392902771
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