Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci

Khanshour, Anas M.; Kou, Ikuyo; Fan, Yanhui; Einarsdottir, Elisabet; Makki, Nadja; Kidane, Yared H.; Kere, Juha; Grauers, Anna; Johnson, Todd A.; Paria, Nandina; Patel, Chandreshkumar; Singhania, Richa; Kamiya, Nobuhiro; Takeda, Kazuki; Otomo, Nao; Watanabe, Kota; Cheung, Kenneth M.C.; Herring, John A.; Rios, Jonathan J.; Ahituv, Nadav; Gerdhem, Paul; Gurnett, Christina A.; Song, You‐Qiang; Ikegawa, Shiro; Wise, Carol A.

doi:10.1093/hmg/ddy306

Cited by 41 publications

(64 citation statements)

References 88 publications

(90 reference statements)

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“…We also identified transcriptional profiles and novel genetic networks of important AIS genes. For example, the genetic network surrounding ADGRG6, an important AIS susceptibility gene (4,5,13), showed interactions with several other genes that have been implicated in AIS, with one of these genes being SOX9, a master regulator of chondrogenesis (24). This interaction is supported by direct observation that loss of Adgrg6 in the IVD is associated with reduced SOX9 expression in cartilaginous endplate and annulus fibrosus regions of the IVD in mouse (21).…”

Section: Discussionmentioning

confidence: 90%

“…One enhancer is located in the fourth intron and one in the 3'UTR of ADGRG6 and a third enhancer is located in the third intron of BNC2 overlapping an alternative promoter. The ADGRG6 and BNC2 loci were found to be associated with AIS both via GWAS and animal studies (4,5,8,13). Additional work on how these loci could affect their expression and subsequent function would be of interest.…”

Section: Discussionmentioning

confidence: 99%

“…To systematically identify genes expressed in AIS-relevant tissues, we carried out RNA-seq on human cartilage, muscle and bone and on mouse IVDs, connective tissue and chondrocytes (as we were not able to obtain equivalent human tissues) ( Fig 1). The above tissues were chosen as they are implicated in AIS-susceptibility through GWAS and animal studies (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). RNA was collected from three biological replicates of each tissue, reverse transcribed and sequenced.…”

Section: Expression Profiling Of Ais Relevant Tissues Identifies Ais-mentioning

confidence: 99%

“…Genome-wide association studies (GWAS) identified at least thirteen genetic loci underlying AIS susceptibility (4)(5)(6)(7)(8)(9)(10)(11)(12), all of which reside within noncoding regions of the genome. These results suggest that nucleotide changes in gene regulatory sequences such as enhancers could be potential drivers of AIS susceptibility (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Makki

Jin

Eckalbar

et al. 2020

Preprint

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Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AISassociated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Expression Profiling Of Ais Relevant Tissues Identifies Ais-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Makki

Jin

Eckalbar

et al. 2020

Preprint

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“…Further, pathway enrichment analysis of a recent multiethnic GWAS meta-analysis provided statistically significant evidence that biologic processes of cartilage development and/ or maintenance are impacted in AIS. 67 An association distal to the PAX1 gene was originally discovered by a GWAS in 3 102 individuals of European descent (North American) and replicated in independent North American, Japanese, and East Asian female cohorts. 68 Further investigation revealed that the association was driven almost entirely by females (combined rs6137473 P = 2.15 × 10 −10 , OR = 1.30) but not males (combined rs6137473 P = 0.71, OR = 1.08), identifying it as an apparently sex-specific AIS locus.…”

Section: Pathways Of Ivd Development and Susceptibility To Adolescentmentioning

confidence: 97%

The cartilage matrisome in adolescent idiopathic scoliosis

et al. 2020

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The human spinal column is a dynamic, segmented, bony, and cartilaginous structure that protects the neurologic system and simultaneously provides balance and flexibility. Children with developmental disorders that affect the patterning or shape of the spine can be at risk of neurologic and other physiologic dysfunctions. The most common developmental disorder of the spine is scoliosis, a lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied understanding in part due to its genetic complexity. Breakthroughs have come from recent genome-wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts, as well as investigations of animal models. These studies have identified genetic associations with determinants of cartilage biogenesis and development of the intervertebral disc (IVD). Current evidence suggests that a fraction of AIS cases may arise from variation in factors involved in the structural integrity and homeostasis of the cartilaginous extracellular matrix (ECM). Here, we review the development of the spine and spinal cartilages, the composition of the cartilage ECM, the so-called "matrisome" and its functions, and the players involved in the genetic architecture of AIS. We also propose a molecular model by which the cartilage matrisome of the IVD contributes to AIS susceptibility.Bone Research (2020) 8:13; https://doi.

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Interrogating Causal Effects of Body Composition and Puberty‐Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two‐Sample Mendelian Randomization Study

Ghanbari,

Otomo,

Gamache

et al. 2023

JBMR Plus

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Adolescent idiopathic scoliosis (AIS) is the most common form of pediatric musculoskeletal disorder. Observational studies have pointed to several risk factors for AIS, but almost no evidence exists to support their causal association with AIS. Here, we applied Mendelian randomization (MR), known to limit bias from confounding and reverse causation, to investigate causal associations between body composition and puberty‐related exposures and AIS risk in Europeans and Asians. For our two‐sample MR studies, we used single nucleotide polymorphisms (SNPs) associated with body mass index (BMI), waist‐hip ratio, lean mass, childhood obesity, bone mineral density (BMD), 25‐hydroxyvitamin D (25OHD), age at menarche, and pubertal growth in large European genome‐wide association studies (GWAS), and with adult osteoporosis risk and age of menarche in Biobank Japan. We extracted estimates of the aforementioned SNPs on AIS risk from the European or Asian subsets of the largest multiancestry AIS GWAS (N = 7956 cases/88,459 controls). The results of our inverse variance‐weighted (IVW) MR estimates suggest no causal association between the aforementioned risk factors and risk of AIS. Pleiotropy‐sensitive MR methods yielded similar results. However, restricting our analysis to European females with AIS, we observed a causal association between estimated BMD and the risk of AIS (IVW odds ratio for AIS = 0.1, 95% confidence interval 0.01 to 0.7, p = 0.02 per SD increase in estimated BMD), but this association was no longer significant after adjusting for BMI, body fat mass, and 25OHD and remained significant after adjusting for age at menarche in multivariable MR. In conclusion, we demonstrated a protective causal effect of BMD on AIS risk in females of European ancestry, but this effect was modified by BMI, body fat mass, and 25OHD levels. Future MR studies using larger AIS GWAS are needed to investigate small effects of the aforementioned exposures on AIS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci

Cited by 41 publications

References 88 publications

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

The cartilage matrisome in adolescent idiopathic scoliosis

Interrogating Causal Effects of Body Composition and Puberty‐Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two‐Sample Mendelian Randomization Study

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