Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis

Jillian G Buchan; David M Alvarado; Gabe E Haller; Carlos Cruchaga; Matthew B Harms; Tianxiao Zhang; Marcia C Willing; Dorothy K Grange; Alan C Braverman; Nancy H Miller; Jose A Morcuende; Nelson Leung-Sang Tang; Tsz-Ping Lam; Bobby Kin-Wah Ng; Jack Chun-Yiu Cheng; Matthew B Dobbs; Christina A Gurnett

doi:10.1093/hmg/ddu224

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Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis

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Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis

Jillian G Buchan, David M Alvarado, Gabe E Haller, Carlos Cruchaga, Matthew B Harms, Tianxiao Zhang, Marcia C Willing, Dorothy K Grange, Alan C Braverman, Nancy H Miller, …

Human molecular genetics, Vol.23(19), pp.5271-5282

10/01/2014

DOI: 10.1093/hmg/ddu224

PMCID: PMC4159151

PMID: 24833718

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Abstract

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.

Phosphorylation

Scoliosis - genetics

Humans

Male

Case-Control Studies

Genetic Variation

Young Adult

Adult

Female

Odds Ratio

Child

Fibrillin-2

Microfilament Proteins - genetics

Severity of Illness Index

Fibrillin-1

Genetic Predisposition to Disease

Genetic Association Studies

Smad2 Protein - metabolism

Fibrillins

Paraspinal Muscles - metabolism

Scoliosis - metabolism

Continental Population Groups - genetics

Marfan Syndrome - genetics

Adolescent

Alleles

Marfan Syndrome - diagnosis

Amino Acid Substitution

Scoliosis - diagnosis

Details

Title: Subtitle: Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis
Creators: Jillian G Buchan - Department of Genetics
David M Alvarado - Department of Orthopaedic Surgery
Gabe E Haller - Department of Orthopaedic Surgery
Carlos Cruchaga - Department of Psychiatry
Matthew B Harms - Department of Neurology
Tianxiao Zhang - Department of Psychiatry
Marcia C Willing - Department of Pediatrics
Dorothy K Grange - Department of Pediatrics
Alan C Braverman - Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Nancy H Miller - Department of Orthopaedic Surgery, University of Colorado, Denver, CO 80202, USA
Jose A Morcuende - Department of Orthopaedic Surgery, University of Iowa, Iowa City, IA 52242, USA
Nelson Leung-Sang Tang - The Chinese University of Hong Kong, Hong Kong, China and
Tsz-Ping Lam - The Chinese University of Hong Kong, Hong Kong, China and
Bobby Kin-Wah Ng - The Chinese University of Hong Kong, Hong Kong, China and
Jack Chun-Yiu Cheng - The Chinese University of Hong Kong, Hong Kong, China and
Matthew B Dobbs - Department of Orthopaedic Surgery St. Louis Shriners Hospital for Children, St. Louis, MO 63131, USA
Christina A Gurnett - Department of Orthopaedic Surgery Department of Neurology Department of Pediatrics, gurnettc@neuro.wustl.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.23(19), pp.5271-5282
Publisher: England
DOI: 10.1093/hmg/ddu224
PMID: 24833718
PMCID: PMC4159151
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: RC2 HL103010 / NHLBI NIH HHS HL-102923 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS UC2 HL102926 / NHLBI NIH HHS P30 CA91842 / NCI NIH HHS RC2 HL102923 / NHLBI NIH HHS HL-103010 / NHLBI NIH HHS RC2 HL102926 / NHLBI NIH HHS UC2 HL103010 / NHLBI NIH HHS UC2 HL102925 / NHLBI NIH HHS HL-102925 / NHLBI NIH HHS UC2 HL102924 / NHLBI NIH HHS UL1 TR001082 / NCATS NIH HHS R01 AG044546 / NIA NIH HHS HL-102926 / NHLBI NIH HHS HL-102924 / NHLBI NIH HHS P30 CA091842 / NCI NIH HHS UL1 RR024992 / NCRR NIH HHS UC2 HL102923 / NHLBI NIH HHS RC2 HL102925 / NHLBI NIH HHS UL1RR024992 / NCRR NIH HHS
Language: English
Date published: 10/01/2014
Academic Unit: Stead Family Department of Pediatrics; Orthopedics and Rehabilitation
Record Identifier: 9984040488502771

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