TY - JOUR
T1 - A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis
AU - Justice, Cristina M.
AU - Cuellar, Araceli
AU - Bala, Krithi
AU - Sabourin, Jeremy A.
AU - Cunningham, Michael L.
AU - Crawford, Karen
AU - Phipps, Julie M.
AU - Zhou, Yan
AU - Cilliers, Deirdre
AU - Byren, Jo C.
AU - Johnson, David
AU - Wall, Steven A.
AU - Morton, Jenny E. V.
AU - Noons, Peter
AU - Sweeney, Elizabeth
AU - Weber, Astrid
AU - Weber, Bertram
AU - Rees, Katie E. M.
AU - Wilson, Louise C.
AU - Simeonov, Emil
AU - Kaneva, Radka
AU - Yaneva, Nadezhda
AU - Georgiev, Kiril
AU - Bussarsky, Assen
AU - Senders, Craig
AU - Zwienenberg, Marike
AU - Boggan, James
AU - Roscioli, Tony
AU - Tamburrini, Gianpiero
AU - Barba, Marta
AU - Conway, Kristin
AU - Sheffield, Val C.
AU - Brody, Lawrence
AU - Mills, James L.
AU - Kay, Denise
AU - Sicko, Robert J.
AU - Langlois, Peter H.
AU - Tittle, Rachel K.
AU - Botto, Lorenzo D.
AU - Jenkins, Mary M.
AU - Lasalle, Janine M.
AU - Lattanzi, Wanda
AU - Wilkie, Andrew O. M.
AU - Wilson, Alexander F.
AU - Romitti, Paul A.
AU - Boyadjiev, Simeon A.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - GWAS
KW - craniosynostosis
KW - genome‑wide association study
KW - non syndromic craniosynostosis
KW - single nucleotide polymorphisms
KW - GWAS
KW - craniosynostosis
KW - genome‑wide association study
KW - non syndromic craniosynostosis
KW - single nucleotide polymorphisms
UR - http://hdl.handle.net/10807/153074
U2 - 10.1007/s00439-020-02157-z
DO - 10.1007/s00439-020-02157-z
M3 - Article
SN - 0340-6717
SP - N/A-N/A
JO - Human Genetics
JF - Human Genetics
ER -