A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

Douglas Londono; Ikuyo Kou; Todd A Johnson; Swarkar Sharma; Yoji Ogura; Tatsuhiko Tsunoda; Atsushi Takahashi; Morio Matsumoto; John A Herring; Tsz-Ping Lam; Xingyan Wang; Elisa M S Tam; You-Qiang Song; Yan-Hui Fan; Danny Chan; Kathryn S E Cheah; Xusheng Qiu; Hua Jiang; Dongsheng Huang; TSRHC IS Clinical Group; International Consortium for Scoliosis Genetics; Peiqiang Su; Pak Sham; Kenneth M C Cheung; Keith D K Luk; Derek Gordon; Yong Qiu; Jack Cheng; Nelson Tang; Shiro Ikegawa; Carol A Wise; Japanese Scoliosis Clinical Research Group; Benny Dahl

doi:10.1136/jmedgenet-2013-102067

A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

Douglas Londono, Ikuyo Kou, Todd A Johnson, Swarkar Sharma, Yoji Ogura, Tatsuhiko Tsunoda, Atsushi Takahashi, Morio Matsumoto, John A Herring, Tsz-Ping Lam, Xingyan Wang, Elisa M S Tam, You-Qiang Song, Yan-Hui Fan, Danny Chan, Kathryn S E Cheah, Xusheng Qiu, Hua Jiang, Dongsheng Huang, TSRHC IS Clinical GroupInternational Consortium for Scoliosis Genetics, Peiqiang Su, Pak Sham, Kenneth M C Cheung, Keith D K Luk, Derek Gordon, Yong Qiu, Jack Cheng, Nelson Tang, Shiro Ikegawa, Carol A Wise, Japanese Scoliosis Clinical Research Group, Benny Dahl

Department of Orthopaedics Surgery

76 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Medical Genetics
Volume	51
Issue number	6
Pages (from-to)	401-6
Number of pages	6
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2013-102067
Publication status	Published - Jun 2014

Keywords

Adolescent
Asian Continental Ancestry Group
Female
Genome-Wide Association Study
Homeodomain Proteins
Humans
Linkage Disequilibrium
Male
Polymorphism, Single Nucleotide
Scoliosis
Transcription Factors

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Londono, D., Kou, I., Johnson, T. A., Sharma, S., Ogura, Y., Tsunoda, T., Takahashi, A., Matsumoto, M., Herring, J. A., Lam, T.-P., Wang, X., Tam, E. M. S., Song, Y.-Q., Fan, Y.-H., Chan, D., Cheah, K. S. E., Qiu, X., Jiang, H., Huang, D., ... Dahl, B. (2014). A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups. Journal of Medical Genetics, 51(6), 401-6. https://doi.org/10.1136/jmedgenet-2013-102067

Londono, D, Kou, I, Johnson, TA, Sharma, S, Ogura, Y, Tsunoda, T, Takahashi, A, Matsumoto, M, Herring, JA, Lam, T-P, Wang, X, Tam, EMS, Song, Y-Q, Fan, Y-H, Chan, D, Cheah, KSE, Qiu, X, Jiang, H, Huang, D, TSRHC IS Clinical Group, International Consortium for Scoliosis Genetics, Su, P, Sham, P, Cheung, KMC, Luk, KDK, Gordon, D, Qiu, Y, Cheng, J, Tang, N, Ikegawa, S, Wise, CA, Japanese Scoliosis Clinical Research Group & Dahl, B 2014, 'A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups', Journal of Medical Genetics, vol. 51, no. 6, pp. 401-6. https://doi.org/10.1136/jmedgenet-2013-102067

@article{dd95e1db2ac048e4b0e2f1ec98e411f4,

title = "A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups",

abstract = "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.",

keywords = "Adolescent, Asian Continental Ancestry Group, Female, Genome-Wide Association Study, Homeodomain Proteins, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Scoliosis, Transcription Factors",

author = "Douglas Londono and Ikuyo Kou and Johnson, \{Todd A\} and Swarkar Sharma and Yoji Ogura and Tatsuhiko Tsunoda and Atsushi Takahashi and Morio Matsumoto and Herring, \{John A\} and Tsz-Ping Lam and Xingyan Wang and Tam, \{Elisa M S\} and You-Qiang Song and Yan-Hui Fan and Danny Chan and Cheah, \{Kathryn S E\} and Xusheng Qiu and Hua Jiang and Dongsheng Huang and \{TSRHC IS Clinical Group\} and \{International Consortium for Scoliosis Genetics\} and Peiqiang Su and Pak Sham and Cheung, \{Kenneth M C\} and Luk, \{Keith D K\} and Derek Gordon and Yong Qiu and Jack Cheng and Nelson Tang and Shiro Ikegawa and Wise, \{Carol A\} and \{Japanese Scoliosis Clinical Research Group\} and Benny Dahl",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2014",

month = jun,

doi = "10.1136/jmedgenet-2013-102067",

language = "English",

volume = "51",

pages = "401--6",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "6",

}

TY - JOUR

T1 - A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

AU - Londono, Douglas

AU - Kou, Ikuyo

AU - Johnson, Todd A

AU - Sharma, Swarkar

AU - Ogura, Yoji

AU - Tsunoda, Tatsuhiko

AU - Takahashi, Atsushi

AU - Matsumoto, Morio

AU - Herring, John A

AU - Lam, Tsz-Ping

AU - Wang, Xingyan

AU - Tam, Elisa M S

AU - Song, You-Qiang

AU - Fan, Yan-Hui

AU - Chan, Danny

AU - Cheah, Kathryn S E

AU - Qiu, Xusheng

AU - Jiang, Hua

AU - Huang, Dongsheng

AU - TSRHC IS Clinical Group, null

AU - International Consortium for Scoliosis Genetics, null

AU - Su, Peiqiang

AU - Sham, Pak

AU - Cheung, Kenneth M C

AU - Luk, Keith D K

AU - Gordon, Derek

AU - Qiu, Yong

AU - Cheng, Jack

AU - Tang, Nelson

AU - Ikegawa, Shiro

AU - Wise, Carol A

AU - Japanese Scoliosis Clinical Research Group

AU - Dahl, Benny

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - Adolescent

KW - Asian Continental Ancestry Group

KW - Female

KW - Genome-Wide Association Study

KW - Homeodomain Proteins

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Scoliosis

KW - Transcription Factors

UR - https://www.scopus.com/pages/publications/84901249776

U2 - 10.1136/jmedgenet-2013-102067

DO - 10.1136/jmedgenet-2013-102067

M3 - Journal article

C2 - 24721834

SN - 0022-2593

VL - 51

SP - 401

EP - 406

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 6

ER -

A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

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Keywords

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