A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.,Human Genetics

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A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.
Human Genetics ( IF 3.8 ) Pub Date : 2020-04-07 , DOI: 10.1007/s00439-020-02157-z
Cristina M Justice ₁ , Araceli Cuellar ₂ , Krithi Bala ₂ , Jeremy A Sabourin ₁ , Michael L Cunningham ₃ , Karen Crawford ₄ , Julie M Phipps _{4,

5} , Yan Zhou ₄ , Deirdre Cilliers ₅ , Jo C Byren ₆ , David Johnson ₆ , Steven A Wall ₆ , Jenny E V Morton _{7,

8} , Peter Noons ₈ , Elizabeth Sweeney ₉ , Astrid Weber ₉ , Katie E M Rees ₁₀ , Louise C Wilson ₁₀ , Emil Simeonov ₁₁ , Radka Kaneva ₁₂ , Nadezhda Yaneva ₁₃ , Kiril Georgiev ₁₄ , Assen Bussarsky ₁₄ , Craig Senders ₁₅ , Marike Zwienenberg ₁₆ , James Boggan ₁₆ , Tony Roscioli ₁₇ , Gianpiero Tamburrini _{18,

19} , Marta Barba _{18,

20} , Kristin Conway ₂₁ , Val C Sheffield ₂₂ , Lawrence Brody ₂₃ , James L Mills ₂₄ , Denise Kay ₂₅ , Robert J Sicko ₂₅ , Peter H Langlois ₂₆ , Rachel K Tittle ₂₇ , Lorenzo D Botto ₂₈ , Mary M Jenkins ₂₉ , Janine M LaSalle ₃₀ , Wanda Lattanzi _{18,

20} , Andrew O M Wilkie _{4,

5,

6} , Alexander F Wilson ₁ , Paul A Romitti ₂₁ , Simeon A Boyadjiev ₂ ,

Affiliation

Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH, Baltimore, MD, USA.
Department of Pediatrics, University of California Davis, 4625 2nd Avenue, Research Building II, Sacramento, CA, 95817, USA.
Department of Pediatrics, Division of Craniofacial Medicine, Seattle Children's Craniofacial Center, Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.
MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
Birmingham Craniofacial Unit, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, England, UK.
Clinical Genetics Service, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.
National Institute of Pediatrics, Sofia Medical University, Sofia, Bulgaria.
Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria.
National Genetic Laboratory, University Hospital of Obstetrics and Gynecology "Maichin Dom", Medical University of Sofia, Sofia, Bulgaria.
Department of Neurosurgery, University Hospital 'St. Ivan Rilski', Medical University of Sofia, Sofia, Bulgaria.
Department of Otolaryngology, Head and Neck Surgery, University of California Davis, Sacramento, CA, USA.
Department of Neurosurgery, University of California Davis, Sacramento, CA, USA.
Neuroscience Research Australia, University of New South Wales, Sydney, Australia.
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Section of Neurosurgery, Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
Section of Experimental Biology, Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
Department of Epidemiology, College of Public Health, The University of Iowa, 145 N Riverside Dr, S416 CPHB, Iowa City, IA, 52242, USA.
Department of Pediatrics, Division of Medical Genetics, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
Gene and Environment Interaction Section, NHGRI, Bethesda, NIHMD, USA.
Epidemiology Branch, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA.
Division of Genetics, NYS Department of Health, Wadsworth CenterAlbany, NY, USA.
Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, TX, USA.
Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA.
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Department of Medical Microbiology and Immunology, Genome Center, and MIND Institute, University of California Davis, Davis, CA, USA.

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^–8): rs781716 (P = 4.71 × 10^–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10^–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10^–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10^–8, OR = 0.45; P = 3.31 × 10^–8, OR = 0.45; P = 1.09 × 10^–8, 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^–8, 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^–6). 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.

中文翻译：

一项全基因组关联研究表明 BMP7 基因座是非综合征性异位颅缝早闭的危险因素。

我们之前针对矢状非综合征性颅缝早闭 (sNCS) 的全基因组关联研究 (GWAS) 为中线 CS 的遗传学提供了重要见解。在这项研究中，我们使用 215 名非西班牙裔白人病例父母三联征，对第二个中线 NCS、同位 NCS (mNCS) 进行了 GWAS。我们鉴定了六个具有全基因组显着性的变体 ( P ≤ 5 × 10 ^–8 )： rs781716 ( P = 4.71 × 10 ^–9 ；比值比 [OR] = 2.44) 是SPRY3的内含子； rs6127972 ( P = 4.41 × 10 ^–8 ; OR = 2.17) 是BMP7 的内含子； rs62590971（ P = 6.22 × 10 ^–9 ；OR = 0.34），位于TGIF2LX上游约 155 kb 处； rs2522623、rs2573826 和 rs2754857，均是PCDH11X的内含子（分别为P = 1.76 × 10 ^–8 ，OR = 0.45； P = 3.31 × 10 ^–8 ，OR = 0.45； P = 1.09 × 10 ^–8 ，OR = 0.44 ）。我们使用由 194 名不相关 mNCS 病例和 333 名未受影响的对照组成的独立非西班牙裔白人样本对这些变异进行了重复研究；仅重复了 rs6127972 的关联（ P = 0.004，OR = 1.45；荟萃分析P = 1.27 × 10 ^–8 ，OR = 1.74）。我们对 mNCS 和 sNCS 研究中常见的单核苷酸多态性进行荟萃分析，结果显示 rs6127972 的关联性最强 ( P = 1.16 × 10 ^–6 )。我们的插补分析发现了一个包含 rs6127972 的连锁不平衡块，该块包含一个与 CTCF 转录因子结合位点 (chr20:55,798,821–55,798,917) 重叠的增强子，与来自相同先证者的开放缝线相比，该增强子在源自融合异位的间充质干细胞中显着低甲基化。这项研究为中线 CS 的遗传因素提供了更多见解。

更新日期：2020-04-07

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