A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups.
BACKGROUND
Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG).


METHODS
Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts.


RESULTS
We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes.


CONCLUSIONS
Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.
Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, USA.
Douglas
D
Londono
Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
Ikuyo
I
Kou
Laboratory for Medical Science Mathematics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
Todd A
TA
Johnson
Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, USA School of Biotechnology, SMVDU, Katra, India.
Swarkar
S
Sharma
Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
Yoji
Y
Ogura
Laboratory for Medical Science Mathematics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
Tatsuhiko
T
Tsunoda
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Yokohama, Japan.
Atsushi
A
Takahashi
Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
Morio
M
Matsumoto
Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, USA Department of Orthopaedics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA.
John A
JA
Herring
Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China Joint Scoliosis Research Center, The Chinese University of Hong Kong and Nanjing University, Hong Kong, China.
Tsz-Ping
TP
Lam
Functional Genomics and Biostatistical Computing Laboratory, Shenzhen Research Institute of the Chinese University of Hong Kong, Hong Kong, China Department of Chemical Pathology, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Xingyan
X
Wang
Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China Joint Scoliosis Research Center, The Chinese University of Hong Kong and Nanjing University, Hong Kong, China.
Elisa M S
EM
Tam
Department of Biochemistry, University of Hong Kong, Hong Kong, China.
You-Qiang
YQ
Song
Department of Biochemistry, University of Hong Kong, Hong Kong, China.
Yan-Hui
YH
Fan
Department of Biochemistry, University of Hong Kong, Hong Kong, China.
Danny
D
Chan
Department of Biochemistry, University of Hong Kong, Hong Kong, China.
Kathryn S E
KS
Cheah
Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Xusheng
X
Qiu
Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Hua
H
Jiang
Department of Orthopedics, The Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
Dongsheng
D
Huang
TSRHC IS Clinical Group
International Consortium for Scoliosis Genetics
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Peiqiang
P
Su
Department of Psychiatry, University of Hong Kong, Hong Kong, China.
Pak
P
Sham
Department of Orthopaedics and Traumatology, University of Hong Kong, Hong Kong, China.
Kenneth M C
KM
Cheung
Department of Orthopaedics and Traumatology, University of Hong Kong, Hong Kong, China.
Keith D K
KD
Luk
Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, USA.
Derek
D
Gordon
Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Yong
Y
Qiu
Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China Joint Scoliosis Research Center, The Chinese University of Hong Kong and Nanjing University, Hong Kong, China.
Jack
J
Cheng
Functional Genomics and Biostatistical Computing Laboratory, Shenzhen Research Institute of the Chinese University of Hong Kong, Hong Kong, China Department of Chemical Pathology, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Nelson
N
Tang
Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
Shiro
S
Ikegawa
Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, USA Department of Orthopaedics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, USA.
Carol A
CA
Wise
D000293:Adolescent; D044466:Asian People / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012600:Scoliosis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C542809:LBX1 protein, human; D014157:Transcription Factors
10q24.31; LBX1; meta-analysis; scoliosis