TY - JOUR
T1 - Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis
AU - Buchan, Jillian G.
AU - Alvarado, David M.
AU - Haller, Gabe E.
AU - Cruchaga, Carlos
AU - Harms, Matthew B.
AU - Zhang, Tianxiao
AU - Willing, Marcia C.
AU - Grange, Dorothy K.
AU - Braverman, Alan C.
AU - Miller, Nancy H.
AU - Morcuende, Jose A.
AU - Tang, Nelson L.eung Sang
AU - Lam, Tsz Ping
AU - Ng, Bobby K.in Wah
AU - Cheng, Jack C.hun Yiu
AU - Dobbs, Matthew B.
AU - Gurnett, Christina A.
N1 - Publisher Copyright:
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis using exome sequence data, we identified fibrillin-1 (FBN1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6)). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P = 0.0035) and upregulation of the transforming growth factor beta pathway. Overall, these results expand our definition of fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.
AB - Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis using exome sequence data, we identified fibrillin-1 (FBN1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6)). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P = 0.0035) and upregulation of the transforming growth factor beta pathway. Overall, these results expand our definition of fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.
UR - http://www.scopus.com/inward/record.url?scp=84964315986&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu224
DO - 10.1093/hmg/ddu224
M3 - Article
C2 - 24833718
AN - SCOPUS:84964315986
SN - 0964-6906
VL - 23
SP - 5271
EP - 5282
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
ER -