Advances in genetic factors of adolescent idiopathic scoliosis: a bibliometric analysis

Objective This study offers a bibliometric analysis of the current situation, hotspots, and cutting-edge domains of genetic factors of adolescent idiopathic scoliosis (AIS). Methods All publications related to genetic factors of AIS from January 1, 1992, to February 28, 2023, were searched from the Web of Science. CiteSpace software was employed for bibliometric analysis, collecting information about countries, institutions, authors, journals, and keywords of each article. Results A cumulative number of 308 articles have been ascertained. Since 2006, publications relating to genetic factors of AIS have significantly increased. China leads in both productivity and influence in this area, with the Chinese Academy of Medical Sciences being the most productive institution. The most prolific scholars in this field are Y. Qiu and Z. Z. Zhu. The publications that contributed the most were from Spine and European Spine Journal. The most prominent keywords in the genetic factors of AIS were “fibrillin gene”, “menarche”, “calmodulin”, “estrogen receptor gene”, “linkage analysis”, “disc degeneration”, “bone mineral density”, “melatonin signaling dysfunction”, “collagen gene”, “mesenchymal stem cell”, “LBX1”, “promoter polymorphism”, “Bone formation”, “cerebrospinal fluid flow” and “extracellular matrix”. Conclusion This analysis provides the frontiers and trends of genetic factors in AIS, including relevant research, partners, institutions and countries.


Introduction
Adolescent idiopathic scoliosis (AIS) is a tridimensional structural abnormality of the spine; that impacts adolescents from 10 years old to maturity (1,2).The main diagnosis is based on the coronal curved Cobb angle, which must be >10°on standard anterior and posterior radiographs (3).AIS affects 1%-4% of teenagers (2), and is more common in girls (3).It can lead to high and low shoulders, trunk displacement, and other appearance deformities (2,4).The development of AIS involves a variety of factors such as genetics, tissues, spinal biomechanics, and hormones (5).Of these, genetics is the major factor.Early identification of relevant genetic variants can help in the diagnosis and prevention of the disease.
Bibliometrics evaluates published research and predicts research trends (6).It can analyze scientific movements, including relationships among countries, institutions, authors, journals, and keywords (7), and has been widely used in various fields.The knowledge map examines the progress and boundaries of the discipline, facilitating researchers to understand the research hotspots and guiding them in their research directions.
Although various studies have focused on the genetic factors of AIS, bibliometric analysis remains scarce.The purpose of this study is to organize relevant studies of AIS genetic factors from January 1, 1992, to February 28, 2023.It summarizes genetic factors and provides researchers with a macro perspective in this area of research.The study includes analysis of the quantity of published articles, associations and symbioses between authors or countries, co-citation of references, and hot areas associated with keywords in the global research and analysis of genetic factors of AIS.

Method Data sources
All data are obtained from the core collection of the Internet database Web of Science (WoS).The literature on genetic factors of AIS published from January 1, 1992, to February 28, 2023, was searched on WoS.Retrieval strategy: TS = ("adolescent idiopathic scoliosis") and TS = (gene or DNA or "base sequence" or "nucleic acid" or "copy number variants" or "single nucleotide polymorphism" or "SNP").The database is updated daily and data are collected in a 24-hour period to prevent potential bias.Primary researches and literature reviews were included.Letters, corrections, meeting abstracts, editorial materials, proceeding papers and book chapters were excluded.

Data analysis
Two separate evaluators (X.W.J. and M.X.Z.) conducted a comprehensive review of the study based on the title and abstract.The compilation and export of references and citations were done in a simple text format.Every bibliographic entry includes a title, author, keywords, abstract and references.
CiteSpace (a Java-based software) was used to perform a bibliometric analysis of the WoS Core Collection.It visualizes information and is frequently employed for evaluating patterns in research (7).It is capable of recognizing leading authors, institutions, and nations, and forming collaborative research connections among these entities.To examine research collaborative connections, a network analysis of references, scholars, and articles using co-citation was proceeded.Extend the co-word network analysis of keywords to provide up-to-theminute viewpoints and research trends.Co-citation relationships show the recurrence with which a terminology or citation is mentioned over a given period.Co-occurrence surges manifest the recurrence with which a keyword or citation appears over a period of time.
The dimensions of the nodes in the visual network graph represent the extent of co-occurrence or recurrence.The line between nodes is the relationship of cooperation, co-occurrence and co-citation.The width and the extent of the lines indicate the proximity of cooperation between nations, organizations, and scholars.The lines depict the relationship among the nodes.Their color shows the publication year.This study is primarily descriptive.Absence of statistics analysis, the quantity and proportion (%) of every index demonstrates the dispersion and change trends of different years, countries, organizations, publications, and scholars.

Publication outputs
Between January 1, 1992, and February 28, 2023, we retrieved a total of 330 records, of which 308 articles were eligible based on inclusion and exclusion criteria.With this group, there were 270 articles classified as original research and 38 articles categorized as reviews.English publications overwhelmingly dominated, accounting for more than 99% (306), while French and German publications were represented by only 1 paper each.From 1992 to 2022, research on AIS genetic factors exhibited a consistent upward trend, with an annual growth rate of 5.93%.The year 2019 stood out as the peak, with the highest number of papers at 40 (Figure 1).Initially, a limited number of publications were observed from 1992 to 2005, but since 2006, there has been a rapid increase.In total, 308 publications garnered 5,771 citations.
Country/region distribution 40 countries have published articles on AIS genetic factors.China was involved in the publication of most articles (50.3%), followed by the United States (25%), Canada (9.4%), Japan (8.8%) and the United Kingdom (4.2%).Figure 2 shows the geographic distribution of publications.Figure 3 shows the cooperation between different regions.Table 1 shows that the H-index (a common indicator of academic influence) (8) of China, the United States, Canada, Japan and the United Kingdom is 28, 27, 14, 18 and 7 respectively.

Institution analysis
Table 2 shows the ranking of institutions involved in publishing articles on genetic factors in AIS.Chinese Academy of Medical Sciences was involved in the largest number of published papers (69; 22.4%), followed by Nanjing University (61; 19.8%),University of Hong Kong (30; 9.7%), RIKEN (21; 6.8%), University of Texas System (21; 6.8%).Figure 4 presents the cooperation among institutions in this field.

Discussion
The research showcases the results of a bibliometric analysis of 308 articles on AIS genetic factors published from January, 1, 1992, to February, 28, 2023 utilizing the WoS database and CiteSpace software.The evolution from 1992 to 2023 is described by 2 phases: 1992-2005, a period of slow growth, and 2006-2023, a phase of swift progress.The number of papers published in 2019 is the largest, but this does not mean that the field has reached its peak.Scholars persist in their field with ongoing research, promising more influential publications ahead.
Analysis of the distribution of countries, institutions and scholars shows international collaboration in this field.According to the article count and the H-index, China stood out as the foremost nation in terms of productivity and impact in AIS genetic factor research.Leveraging its sizable population and proficiency in sample collection from AIS patients, China has witnessed accelerated development in studying AIS genetic factors, propelled by economic, technological, and intellectual advancements.The advancement of the economy has stimulated investment in the healthcare sector, leading to a surge in research productivity (6,9).In addition, young Chinese spine surgeons excel in basic research and article publication.The USA, a powerhouse of economy, science, and technology, assumes a vital role in studying the AIS genetic factors.When analyzing the dispersion of academic papers by nation, organization, and author, Japan was also a noteworthy participant in research efforts.
Qiu Yong and Zhu Zezhang, affiliated with Drum Tower Hospital, Nanjing University, China, have published extensively on this topic.They have maintained a close collaboration.The quantity of co-authors serves as a significant metric for the status of the research.The visual map of this study indicates inadequate connections among countries, institutions, and authors.Enhancing academic collaboration is imperative.Journal analysis assists researchers in selecting appropriate publications.Spine and European Spine Journal are the mainstream journals on the topic.These journals might exhibit greater openness to researching genetic factors in AIS, and manuscripts featured in these journals have higher chances of gaining attention and citations.
Keywords reflect the focus and trajectory of the research.Keyword evolution analysis provides a crucial basis for exploring the research of AIS genetic factors.After removing keywords related to the topic, the most prominent burst keywords of AIS genetic factors are "fibrillin gene", "menarche", "calmodulin", "estrogen receptor gene", "linkage analysis", "disc degeneration", "bone mineral density", "melatonin signaling dysfunction", "collagen gene", "mesenchymal stem cell", "LBX1", "promoter polymorphism", "Bone formation", "cerebrospinal fluid flow" and "extracellular matrix".The results of the burst keywords and clustering revealed that the prominent theme in this field over the last 30 years has been the expression and verification of genes related to the spine and its accessory structures.
Most of the 10 most cited papers investigated the genetic factors of AIS through genome-wide association studies.In 2007, Xu et al. found that the MTNR1B gene is lowly expressed in osteoblasts from AIS patients but is not involved in disease progression (10).Subsequently, AIS-related susceptibility genes continue to emerge, including MATN1 (11), LBX1 (12), PAX1 (13), BNC2 (14) and GPR126 (15,16).Except for the BNC2 gene, all genes were lowly expressed in the tissue cells of AIS patients.AIS-related signaling pathways have also shown remarkable results.Sharma et al. found a possible association between the clinical phenotype of horizontal gaze palsy with progressive scoliosis in patients with compound heterozygous mutations in ROBO3 and the involvement of the ROBO3 gene in the regulation of the axon guidance pathway (17).Zhu et al. found that the proportion of type I fibers was higher on the convex side than on the concave side in patients with AIS, which may be related to the asymmetric expression of the Wnt/βcatenin pathway in the paraspinal muscles on both sides of the spine (18).These studies suggest that AIS may be the result of the combined effects of multiple gene expression and different signaling pathways.
Combining keyword burst analysis and keyword clustering analysis, we summarized the new perspectives of AIS genetic factors research papers published in the last 5 years as: urotensin and its related receptors, cilia, chondrocytes and osteogenesis, muscle tissue, neural crest cells, and connective tissue.

Urotensin and its related receptors
Zebrafish, genetically similar to humans, are ideal subjects for studying scoliosis due to their inherent susceptibility to the condition (19,20).The circulation of cerebrospinal fluid (CSF) is associated with spinal development and can result in zebrafish developing spinal deformities (21)(22)(23).When CSF flows through neurons in contact with CSF(CSF-cNs) in the central canal, these neurons produce the urotensin-related peptides Urp1 and Urp2 (24-26).These peptides can bind to Uts2r receptors on the membrane of dorsal slow-twitch myocytes in zebrafish embryos, causing the myocytes to contract dorsally and straighten the body axis.Reducing these peptides during zebrafish growth causes spinal deformities similar to human spinal dysplasia (27,28).Bearce et al. found that zebrafish lacking Uts2r3 have scoliosis in adulthood; and that Uts2r3, as a receptor of the urotensin family, may regulate spinal morphology (21).Research on Chinese Han patients with AIS has additionally verified a substantial correlation between UTS2R gene mutation and AIS (29).It can be concluded that mutations in the genes that control the production of urotensin and its receptor may lead to the development of AIS.

Cilia
Cilia are hairy organelles positioned outside the cell membrane (30).Active cilia produce cellular motility, drive fluid flow or generate signal gradients (22,31).Cilia assembly and CSF flow are closely associated with AIS (22).Elizabeth et al. suggest that motile cilia in the zebrafish vertebral canal promote the synthesis of Reissner's fibers, which transport epinephrine to the central canal.
Epinephrine acts on CSF-cNs to induce Urp peptides secretion.These urotensins signal the zebrafish dorsal slow-twitch muscles to elicit contractions that resolve the ventral curve and promote spinal straightening (28).The mutation rate of the POC5 gene in French-Canadian and British AIS patients was significantly higher than in normal controls (32).Its aberrant expression affects Urp peptides secretion, which limits the contraction of slow-twitch muscles and imbalances muscle strength on both sides of the spine, causing scoliosis (33).Similarly, variants in the TTLL11 gene were present in the majority of UK families with concomitant scoliosis; a zebrafish model with the gene knocked out replicated this condition (34).Abnormal ciliary movement may also lead to scoliosis.Zebrafish cilia contribute to Reissner fiber aggregation and straightening of the body axis; and knockout of the ciliary polarity and movementrelated gene cfap298 (35) and ciliary dynamic protein axonal heavy chain 10 genes may affect Reissner fiber aggregation and lead to zebrafish spinal deformity (21,36).Variants in genes dnaaf1 and zmynd10 related to cilia structure and function were also found in AIS patients in southern China by whole exome sequencing (37).Knockout of these genes in viable adult zebrafish recapitulated scoliosis (37).It can be concluded that mutations in cilia-related genes cause AIS by impeding CSF flow, Reissner fiber synthesis, and urotensin release allowing an imbalance of paraspinal musculature.

Chondrocytes and osteogenic process
Meta-analyses have summarized and confirmed that AISrelated gene mutations affect chondrocyte development and osteogenesis (such as CDH13, ABO and COMP) (38,39).Among them, COMP gene expression is down-regulated in osteoblasts of AIS patients, which synthesize abnormal proteins with cytotoxicity, triggering chondrocyte underdevelopment or even death, resulting in impaired bone growth (39).A number of studies on signaling pathways involved in the process.The ERK1/ 2 signaling pathway activates the AKAP2 gene, promoting the proliferation and specialization of chondrocytes in the human growth plate, while AKAP2 gene expression was reduced in AIS patients (40).Upregulation of the RHOA gene in AIS patients inhibits the differentiation of MSCs to cartilage through the RHOA/ROCK signaling pathway and hinders bone growth (41).SPRY4 gene is the key to promoting osteogenic differentiation and melatonin response in mesenchymal stem cells.Its overexpression, along with melatonin, enhances osteogenesis, whereas knockout of SPRY4 hampers osteogenesis in AIS patients (42,43).Low expression of ADGRG7, GREM1 and GPR126 genes affects osteogenesis in AIS patients (44)(45)(46)(47).CHD7 and BOC gene expression even positively correlated with bone mineral content in AIS patients (48,49).

Muscle tissue
AIS is often accompanied by differential expression of genes in paraspinal muscle cells.The abnormal expression of the LBX1 gene has been replicated in a large sample of multi-ethnic AIS patients   (50, 51) and successfully verified in mouse experiments (52).Low expression of the LBX1 gene may reduce energy supply to skeletal muscle cells and accelerate disease progression by affecting galactose metabolism and glycolytic pathways (53).Genes also regulate the development of paraspinal muscles.High expression of the TENT5A gene facilitates myofiber maturation by promoting the proliferative migration of myofibroblasts and maintaining the stability of myogenin; whereas, the TENT5A gene is lowly expressed in the paraspinal muscles of patients with AIS (54).In addition to the genes mentioned above, numerous The network of keywords.Nodes represent keywords, lines represent co-occurrence relationships.Colors in the nodes indicate different years.Node size reflects its frequency.
The cluster view map.Each grid contains a cluster of locations.The lower the number, the higher the number of keywords included in the clusters.Top 71 keywords with the strongest citation bursts.The red bar is the burst phase.

Neural crest cell
AIS patients displayed chondroblasts in the curved convex growth plate, while the concave side had neuroblasts and glial blasts (63).Bilateral growth imbalance results in scoliosis.Neural crest cells migrate along a specific pathway during embryonic development to form neuroblasts and glial blasts (63, 64).During migration, neural crest cells experience epithelial-mesenchymal transition (65), facilitating their migration into the mesenchymal extracellular matrix (66).PAX3 gene is linked to the formation of mesenchymal extracellular matrix, including the expression of two multifunctional proteoglycan subtypes (V1 and V0) (67).Multifunctional proteoglycan can guide the migration of neural crest cells (68,69).Cartilage differentiation of mesenchymal cells may influence the migration of neural crest cells (70).Therefore, the PAX3 gene may cause non-synchronous migration of neural crest cells and different phenotypes of cells on both sides of the spine, resulting in idiopathic scoliosis.

Connective tissue
Connective tissue plays a role in maintaining normal spine morphology, including intervertebral discs, ligaments, and tendons (71,72).The ADGRG6 gene regulates the biomechanical structure of intervertebral discs and dense connective tissues to maintain normal spinal morphology through the cAMP/CREB signaling pathway; whereas AIS patients have defective expression of the ADGRG6 gene (73).The expression of the PAX-1 gene in the disc is involved in the formation of the spinal structure (74).In addition, upregulation of ERC2 and MAFB gene expression in AIS patients may promote hypertrophy of the ligamentum flavum to adapt to mechanical stresses generated by scoliosis via the TGF-β pathway (75).The FBN1 gene is crucial for connective tissue function (76), and its low expression reduces the synthesis of extracellular matrix proteins, which is detrimental to maintaining the stability of the biomechanical structure of connective tissues such as ligaments and intervertebral discs, leading to the progression of AIS (77).ADAMTSL2 and LTBPs can bind to FBN1 in vitro and upregulate the TGF-β signaling pathway in fibroblasts (78-81).Ryzhkov et al. found that the TGF-β signaling pathway, which is involved in the formation and degradation of extracellular matrix proteins, is more highly expressed on the concave side of the curve than on the convex side in patients with AIS, and may be involved in the process of disc tissue degeneration (82).Therefore, The interaction between ADAMTSL2 and LTBP4 is involved in the development of AIS through the TGF-β pathway (83).The above results show that connective tissue-related genes are involved in the onset and development of AIS.
Although research on genetic factors associated with AIS is recent and extensive, most studies are not in-depth and have some limitations.
1. Most studies have small sample sizes and selection bias, and the samples can not represent the patient group (33,84).2. Many studies only examine whether there is a correlation, but do not explain the causality and mechanism of action (14,16).3. Some studies are unable to obtain muscle, bone, and other tissues that may be directly related to AIS (85,86).4. Integrating the existing research results and establishing the mathematical model of AIS is beneficial for the diagnosis and prevention of the disease (87).
In the process of studying the etiology of AIS, researchers have gradually recognized that AIS is a disease caused by the combined effects of multiple factors.Over the past few decades, the study of AIS etiology has shifted from a macroscopic to a microscopic level, particularly with the rise of GWAS, which allows for comprehensive screening of genes associated with the occurrence and development of AIS.As a result, various tissues related to AIS have been included in the research.While these studies have provided abundant results, they have been scattered, making it difficult to identify the primary effect genes.Additionally, there is a lack of AIS samples from diverse ethnic backgrounds, preventing integration into a unified system.Artificial intelligence (AI) is well known for its ability to analyze and process large amounts of data, and discover hidden relationships between variables.By consolidating clinical and GWAS data from previous AIS patients and constructing a database that is continuously updated, we can combine the vast clinical information and GWAS data of AIS patients with AI.This integration allows for the training of a dynamic AIS simulation system, which can uncover associations between potential genetic variations and specific clinical phenotypes, predict AIS risk and progression, simulate gene-targeted therapies for AIS, and even customize personalized disease risk assessment models based on individual AIS patients' genomic information and relevant clinical parameters.This approach provides targeted medical advice and treatment plans, contributing to the development of precision medicine and improving treatment outcomes and health management for each patient.

Advantages and constraints of this research
This is an inaugural bibliometric analysis of the genetic factors of AIS.This study discusses the current situation, progress and trend of the role of genetic factors in AIS, so that scholars can focus on the latest and most important hotspots.This study has several limitations.First, there is a temporal delay as this study did not incorporate recent publications.Second, it is not comprehensive.We only looked at articles from the WoS core collection.Finally, subjective bias exists in the interpretation of the results.

Conclusion
Research into the genetic factors of AIS indicates a worldwide pattern over time.Beginning in 2006, there has been a significant surge in the quantity of published research.China and the Chinese Academy of Medical Sciences emerge as the most productive countries and institutions in this regard.A large number of articles have been published in Spine and European Spine Journal.Y. Qiu and Z. Z. Zhu are both prolific authors.The strongest burst keywords among the genetic factors of AIS were "fibrillin gene", "menarche", "calmodulin", "estrogen receptor gene", "linkage analysis", "disc degeneration", "bone mineral density", "melatonin signaling dysfunction", "collagen gene", "mesenchymal stem cell", "LBX1", "promoter polymorphism", "Bone formation", "cerebrospinal fluid flow" and "extracellular matrix".In addition, scholars would find valuable insights from the prominent clusters, highly cited publications and references.

Figure 6
presents the collaboration network of the scholars.Y. Qiu and Z. Z. Zhu contributed to the publication of 59 and 36 papers respectively.The top 3 most cited scholars are Y.Takahashi (113), S. L. Weinstein (111) and N. H. Miller (105).When 2 articles refer to the same article, a common reference link is created.

Figure 7
shows the influential authors associated with the genetic factors of AIS.Authors or co-authors of papers working in identical nations appear in the bibliographic link.

FIGURE 2
FIGURE 2The geographic distribution of publications.Darker colors indicate greater number of publications.

Figure 9
presents the network of keywords.Keyword clustering involves grouping words and phrases that exhibit clear domain characteristics.It utilizes feature extraction algorithms to classify text and perform domain-based clustering of words.By managing word frequency, it identifies both general and specific domain-related terms.

Figure 11
presents the top 71 cited keywords.The red and blue bars indicate common and uncommon keywords correspondingly.The most popular keywords in AIS genetic factors were "fibrillin

FIGURE 3
FIGURE 3 Collaboration network of productive countries/regions.Nodes represent countries/regions, and lines indicate co-citation relationships.Node colors correspond to different years.Larger nodes indicate higher publication numbers.

FIGURE 4
FIGURE 4 Collaboration network of productive institutions.Nodes represent institutions, lines represent co-citation relationships.Node colors indicate different years.Node size reflects publication numbers.

FIGURE 6
FIGURE 6 Collaboration network of productive authors.Nodes represent authors, lines represent collaborations.Node colors indicate different years.Node size reflects publication count.

FIGURE 7
FIGURE 7 Collaboration network of cited authors.Nodes represent co-cited authors.Lines represent co-citation relationships.Node colors indicate different years.Node size reflects the number of co-citations.

TABLE 1
Top 5countries contributed to research publications on the genetic factors of AIS.

TABLE 2
Top 10productive institutions in the genetic factors of AIS.

TABLE 3
Top 10productive journals in the genetic factors of AIS.

TABLE 4
The most productive authors in the genetic factors of AIS.

TABLE 5
Top 10 cited articles in the genetic factors of AIS.