TY - JOUR
T1 - CELSR2 is a candidate susceptibility gene in idiopathic scoliosis
AU - Einarsdottir, Elisabet
AU - Grauers, Anna
AU - Wang, Jingwen
AU - Jiao, Hong
AU - Escher, Stefan A.
AU - Danielsson, Aina
AU - Simony, Ane
AU - Andersen, Mikkel
AU - Christensen, Steen Bach
AU - Åkesson, Kristina
AU - Kou, Ikuyo
AU - Khanshour, Anas M.
AU - Ohlin, Acke
AU - Wise, Carol
AU - Ikegawa, Shiro
AU - Kere, Juha
AU - Gerdhem, Paul
N1 - Funding Information:
This study was financially supported by funds from the Swedish Research Council (number K-2013-52X-22198-01-3), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Department of Research and Development of Västernorrland County Council, the Karolinska Institutet research funds, the Research and Development Council of Region SkÅne, the Swedish Society of Spinal Surgeons, the Visare Norr fund from the Northern County Councils Regional Federation, the Scoliosis Research Society, the Alfred Österlund Foundation and the Emil Andersson Foundation. JK is a recipient of The Royal Society Wolfson Research Excellence Award. Genotyping and analysis of the US cohort was supported by the NIH P01 HD084387 to CW. The authors would like to thank Ingegerd Fransson for expert technical assistance, and Lars Allan Larsen and Malene Rask Andersen for work on the CELSR2 protein. Ripley Högnadóttir and Nysa Grauers are thanked for critical reviewing of the manuscript. Luigi Belcastro is thanked for collection and handling of samples. Ralph Hasserius, Klas Halldin, Pawel Grabow-ski, Max Tenne and Magnus K Karlsson are thanked for help with ScoliGeneS recruitment.
Publisher Copyright:
© 2017 Einarsdottir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/12
Y1 - 2017/12
N2 - A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.
AB - A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.
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U2 - 10.1371/journal.pone.0189591
DO - 10.1371/journal.pone.0189591
M3 - Article
C2 - 29240829
AN - SCOPUS:85038599608
SN - 1932-6203
VL - 12
JO - PloS one
JF - PloS one
IS - 12
M1 - e0189591
ER -