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

Details

• Alternative Title:
  Hum Genet
• Personal Author:
  Justice, Cristina M ; Cuellar, Araceli ; Bala, Krithi ; Sabourin, Jeremy A ; Cunningham, Michael L ; Crawford, Karen ; Phipps, Julie M ; Zhou, Yan ; Cilliers, Deirdre ; Byren, Jo C ; Johnson, David ; Wall, Steven A ; Morton, Jenny E V ; Noons, Peter ; Sweeney, Elizabeth ; Weber, Astrid ; Rees, Katie E M ; Wilson, Louise C ; Simeonov, Emil ; Kaneva, Radka ; Yaneva, Nadezhda ; Georgiev, Kiril ; Bussarsky, Assen ; Senders, Craig ; Zwienenberg, Marike ; Boggan, James ; Roscioli, Tony ; Tamburrini, Gianpiero ; Barba, Marta ; Conway, Kristin ; Sheffield, Val C ; Brody, Lawrence ; Mills, James L ; Kay, Denise ; Sicko, Robert J ; Langlois, Peter H ; Tittle, Rachel K ; Botto, Lorenzo D ; Jenkins, Mary M ; LaSalle, Janine M ; Lattanzi, Wanda ; Wilkie, Andrew O M ; Wilson, Alexander F ; Romitti, Paul A ; Boyadjiev, Simeon A
• Corporate Authors:
  The National Birth Defects Prevention Study
• Description:
  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.
• Subjects:
  Alleles Bone Morphogenetic Protein 7 Craniosynostoses DNA Methylation Genes, Reporter Genetic Predisposition To Disease Genetic Variation Genome-Wide Association Study Genotype Humans Introns Linkage Disequilibrium Polymorphism, Single Nucleotide Promoter Regions, Genetic Risk Factors

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• Source:
  Hum Genet. 139(8):1077-1090
• Pubmed ID:
  32266521
• Pubmed Central ID:
  PMC7415527
• Document Type:
  Journal Article
• Funding:
  R01 DE016886/DE/NIDCR NIH HHSUnited States/ ; U01 DD001223/DD/NCBDD CDC HHSUnited States/ ; DE018277/DE/NIDCR NIH HHSUnited States/ ; FOA #DD09-001/CC/CDC HHSUnited States/ ; U01 DD001223/CC/CDC HHSUnited States/ ; 102731/WT_/Wellcome TrustUnited Kingdom/ ; FOA #DD13-003/CC/CDC HHSUnited States/ ; U01 DD001035/DD/NCBDD CDC HHSUnited States/ ; PA #96043/CC/CDC HHSUnited States/ ; 102731/Z/13/Z/WT_/Wellcome TrustUnited Kingdom/ ; EP-D-18-001/EPA/EPAUnited States/ ; HHSN275201100001I/HD/NICHD NIH HHSUnited States/ ; WT_/Wellcome TrustUnited Kingdom/ ; PA #02081/CC/CDC HHSUnited States/ ; U01 DD001035/CC/CDC HHSUnited States/ ; CDP 13-003/HX/HSRD VAUnited States/ ; HHSN268200782096C/HG/NHGRI NIH HHSUnited States/ ; U01 DD001227/DD/NCBDD CDC HHSUnited States/ ; HHSN275201100001C/HD/NICHD NIH HHSUnited States/ ; HHSN27500005/National Institute of Child Health and Human Development/ ; NOFO #DD18-001/CC/CDC HHSUnited States/ ; HHSN275201100001G/HD/NICHD NIH HHSUnited States/
• Volume:
  139
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:adf14fd670690b6d51d00cead8f6411f88b6b4463aec936715ea1da879274f01
• Download URL:
  https://stacks.cdc.gov/view/cdc/91900/cdc_91900_DS1.pdf
• File Type:
  [PDF - 987.12 KB ]