Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Adolescent idiopathic scoliosis (AIS) is a twisting deformity of the spine that occurs during periods of rapid growth in children worldwide. Children with severe cases of AIS require surgery to stop it from getting worse, presenting a significant financial burden to health systems and families. Although AIS is known to cluster in families, its genetic causes and its inheritance pattern have remained elusive. Additionally, AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. One of the main components of the extracellular matrix is collagen. Yu, Kanshour, Ushiki et al. hypothesized that changes in the extracellular matrix could affect the cartilage and connective tissues of the spine, leading to AIS. To show this, the scientists screened over 100,000 individuals and found that AIS is associated with variants in two genes coding for extracellular matrix proteins. One of these variants was found in a gene called Col11a1, which codes for one of the proteins that makes up collagen. To understand the relationship between Pax1 and Col11a1, Yu, Kanshour, Ushiki et al. genetically modified mice so that they would lack the Pax1 gene. In these mice, the activation of Col11a1 was reduced in the mouse spine. They also found that the form of Col11a1 associated with AIS could not suppress the activation of a gene called Mmp3 in mouse cartilage cells as effectively as unmutated Col11a1. Going one step further, the researchers found that lowering the levels of an estrogen receptor altered the activation patterns of Pax1, Col11a1, and Mmp3 in mouse cartilage cells. These findings suggest a possible mechanism for AIS, particularly in females. The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

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

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.

Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated. Material and methods: Mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese. Results: Significant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI. Conclusions: Our Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS.

Genetic insights into ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); P=7.07e-11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in spinal chondrocytes.

Identification of a Functional Susceptibility Variant for Adolescent Idiopathic Scoliosis that Upregulates Early Growth Response 1 (EGR1)-Mediated UNCX Expression.

Adolescent idiopathic scoliosis (AIS) is a serious health problem affecting 3% of live births all over the world. Many loci associated with AIS have been identified by previous genome wide association studies, but their biological implication remains mostly unclear. In this study, we evaluated the AIS-associated variants in the 7p22.3 locus by combining in silico, in vitro, and in vivo analyses. rs78148157 was located in an enhancer of UNCX, a homeobox gene and its risk allele upregulated the UNCX expression. A transcription factor, early growth response 1 (EGR1), transactivated the rs78148157-located enhancer and showed a higher binding affinity for the risk allele of rs78148157. Furthermore, zebrafish larvae with UNCX messenger RNA (mRNA) injection developed body curvature and defective neurogenesis in a dose-dependent manner. rs78148157 confers the genetic susceptibility to AIS by enhancing the EGR1-regulated UNCX expression. © 2022 American Society for Bone and Mineral Research (ASBMR).

Upper End Vertebra of Proximal Thoracic Curve At T1 is a Novel Risk Factor of Postoperative Shoulder Imbalance in Lenke Type 2 Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Retrospective single-center study. OBJECTIVE: We investigated the risk factors of postoperative shoulder imbalance (PSI) in patients with Lenke type 2 adolescent idiopathic scoliosis (AIS) including the position of preoperative upper end vertebra (UEV). METHODS: Seventy-five patients with Lenke type 2 AIS who underwent posterior correction and fusion surgeries from 2008 to 2018 were included. We included only patients whose upper instrumented vertebrae were at T2. The patients were divided into 2 groups based on radiographic shoulder height (RSH) at final follow-up, namely PSI group and non-PSI group, and PSI was defined as RSH > 10 mm. UEV, RSH, Cobb angle, curve flexibility, T1 and T2 tilt, correction rate, Risser grade, Scoliosis Research Society-22 scores, and demographic data were compared between the groups using independent t-tests or chi-square tests. Variables with P value < 0.20 in univariate analysis were assessed in logistic regression analysis. RESULTS: Thirty-four patients in the PSI group and 37 patients in the non-PSI group were analyzed. Univariate analysis revealed that there were more patients with UEV at T1 (PSI: 85%, non-PSI: 54%, P < 0.01) and Risser grade ≥ 3 (PSI: 88%, non-PSI: 62%; P < 0.05) in the PSI group than in the non-PSI group. Logistic regression analysis revealed that UEV at T1 (odds ratio [OR] = 4.1 [1.2-14.4], P < 0.05) and Risser grade ≥ 3 (OR = 3.9 [1.1-14.5], P < 0.05) are significantly associated with PSI. CONCLUSIONS: UEV at T1 and Risser grade ≥ 3 at the time of surgery are significant risk factors of PSI.

Clinical Results after Release of Sternocleidomastoid Muscle Surgery for Neglected Congenital Muscular Torticollis-Unipolar vs. Bipolar Release Surgery.

BACKGROUND: Although the surgical release of the sternocleidomastoid muscle (SCM) is required for residual congenital muscular torticollis (CMT), the surgical outcomes between bipolar and unipolar SCM release remained unclear. The purpose of the present study was to assess surgical outcomes after bipolar and unipolar release of SCM in adolescent/adult patients with neglected CMT. METHODS: Twenty-one consecutive adolescent/adult patients with neglected CMT who underwent surgical treatment were enrolled. Clinical and radiographic outcomes were evaluated at preoperative and final follow-up. RESULTS: The bipolar release of SCM was performed in 3 patients (B group; males, n = 1, females, n = 2) and the unipolar release of SCM in 18 patients (U group; males, n = 6, females, n = 12). The mean age at surgery was 40.0 ± 17.0 years in Group B, and that was 32.3 ± 13.1 years in Group U (p = 0.47). The mean follow-up period was 16.0 ± 5.7 months in Group B and 10.4 ± 7.6 months in Group U (p = 0.22). Cervicomandibular angle correction rates were comparable at 75.4 ± 2.4% for the B group and 73.1 ± 11.7% for the U group (p = 0.62). There was no significant difference in clinical outcome according to the modified Cheng and Tang score between the two groups (p = 0.89). No major complications arose, although one patient exhibited a transient neurological deficit of the greater auricular nerve, and one patient developed a hematoma in the B group. CONCLUSIONS: The unipolar SCM release appeared to be a non-inferiority and less invasive procedure, minimizing surgical scars and avoiding potential auricular nerve damage in adolescent/adult patients with neglected CMT.

Comparative Study of S2-Alar-Iliac Screw Trajectories between Males and Females Using Three-Dimensional Computed Tomography Analysis: The True Lateral Angulation of the S2-Alar-Iliac Screw in the Axial Plane.

The S2 alar-iliac screw (S2AIS) is commonly used for long spinal fusion as a rigid distal foundation in spinal deformity surgeries, and it is also used in percutaneous sacropelvic fixation for providing an in-line connection to the proximal spinal constructs without using offset connectors. Although the pelvic shape is different between males and females, reports on S2AIS trajectories according to gender have been scarce in the literature. In this paper, S2AIS trajectories are compared between males and females using pelvic three-dimensional computed tomography (3D-CT) in a normal Japanese population. After resetting the caudal angulation in CT-imaging plane manipulation, the angulation of S2AIS was more lateral in the axial plane and more horizontal in the coronal plane in females. Mean distances from the midline to starting points of S2AIS tended to be shorter in females, whereas mean distances from the midline to the posterior superior iliac spine was significantly longer in females. We also found that there were positive correlations between the patients' height and the maximal lengths of S2AISs, and the patients' height and minimal areas of S2AIS pathways. Our results are useful not only for conventional open spinal surgery, but also for minimally invasive spine surgery.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Computed Tomography-Based Navigation System in Current Spine Surgery: A Narrative Review.

The number of spine surgeries using instrumentation has been increasing with recent advances in surgical techniques and spinal implants. Navigation systems have been attracting attention since the 1990s in order to perform spine surgeries safely and effectively, and they enable us to perform complex spine surgeries that have been difficult to perform in the past. Navigation systems are also contributing to the improvement of minimally invasive spine stabilization (MISt) surgery, which is becoming popular due to aging populations. Conventional navigation systems were based on reconstructions obtained by preoperative computed tomography (CT) images and did not always accurately reproduce the intraoperative patient positioning, which could lead to problems involving inaccurate positional information and time loss associated with registration. Since 2006, an intraoperative CT-based navigation system has been introduced as a solution to these problems, and it is now becoming the mainstay of navigated spine surgery. Here, we highlighted the use of intraoperative CT-based navigation systems in current spine surgery, as well as future issues and prospects.

Genome-wide association study of colorectal polyps identified highly overlapping polygenic architecture with colorectal cancer.

No genome-wide association studies (GWAS) were reported for colorectal polyps and the overlap in polygenic backgrounds conferring risk of colorectal cancer and polyps remains unclear. We performed GWAS on subjects with colorectal polyps using the BioBank Japan data with 4447 cases and 157,226 controls. We evaluated genetic correlations between colorectal polyps and cancer, and effects on colorectal polyps of single nucleotide polymorphisms (SNPs) known to be associated with colorectal cancer. We identified CUX2, a known genetic locus to colorectal cancer, as a susceptibility locus to colorectal polyps (p value = 1.1 × 10-15). Subsequent fine-mapping analysis indicated that rs11065828 in CUX2 is the causal variant for colorectal polyps. We found that known colorectal cancer-susceptible SNPs were also associated with colorectal polyps. The genetic correlation between colorectal cancer and polyps is very high (r = 0.98 and p value = 0.0006). We additionally identified 14 significant loci of colorectal polyps and three significant loci of colorectal cancer by applying the multi-trait analysis of GWAS of colorectal cancer and colorectal polyps. We showed very similar germline polygenic features, which gives us the additional insight into potential cancers at polygenic levels for patients with polyps who are followed up at outpatients' clinic; thus, close observation and polypectomy is critical to prevent colorectal cancers.

Surgical Predictors for Prevention of Postoperative Shoulder Imbalance in Lenke Type 2A Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Multicenter, retrospective cohort study. OBJECTIVE: The aim of this study was to investigate the occurrence and surgical predictors of postoperative shoulder imbalance (PSI) in Lenke type 2A adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Although several studies have investigated the factors influencing PSI in Lenke type 2 curves, no studies have analyzed PSI-related factors considering upper instrumented vertebra (UIV) and lumbar modifier type simultaneously. METHODS: Patients with Lenke Type 2A AIS treated by spinal fusion were retrospectively identified and their data were extracted from six spine centers in Japan. Inclusion criteria were age between 10 and 20 years at surgery, UIV = T2, major curve 40° to 90°, and follow-up for 24 to 30 months after surgery. We analyzed patient characteristics, surgical characteristics, and preoperative and immediate-postoperative radiographic parameters. We defined patients with lower instrumented vertebra (LIV) equal or proximal to the last touching vertebra (LTV) as selective thoracic fusion (STF-LTV) and patients with LIV distal to the LTV as non-STF-LTV. t Tests, Mann-Whitney U test, χ2 tests, Fisher exact tests, and multivariate logistic regression were used for statistical analyses. RESULTS: Among the 99 consecutive patients with a mean follow-up of 25.6 months, PSI was seen in 27 (27.3%) patients immediately after and in 17 (17.2%) patients at 24 to 30 months. The univariate analysis revealed that the significant risk factors of PSI were preoperative radiographical shoulder height, non-STF-LTV, and high main thoracic curve (MTC) correction (immediate-postoperative MTC correction rate: ≥70%), with PSI incidence of 40.0%. The multivariate logistic regression analysis indicated that interaction term of non-STF-LTV and high MTC correction was an independent risk factor for PSI (non-STF-LTV and high MTC correction, odds ratio: 5.167, 95% confidence interval: 1.470-18.159, P = 0.010). CONCLUSION: To prevent PSI in Lenke Type 2A AIS patients, surgeons should avoid the combination of non-STF-LTV and high MTC correction in those surgeries with UIV as T2.Level of Evidence: 4.

Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use.

Adolescent idiopathic scoliosis (AIS) is a common disease causing three-dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.5% in twin studies, prediction of its onset and progression based on genetic data is a promising option. We show the usefulness of polygenic risk score (PRS) for the prediction of onset and progression of AIS. We used AIS genomewide association study (GWAS) data comprising 79,211 subjects in three cohorts and constructed a PRS based on association statistics in a discovery set including 31,999 female subjects. After calibration using a validation data set, we applied the PRS to a test data set. By integrating functional annotations showing heritability enrichment in the selection of variants, the PRS demonstrated an association with AIS susceptibility (p = 3.5 × 10-40 with area under the receiver-operating characteristic [AUROC] = 0.674, sensitivity = 0.644, and specificity = 0.622). The decile with the highest PRS showed an odds ratio of as high as 3.36 (p = 1.4 × 10-10 ) to develop AIS compared with the fifth in decile. The addition of a predictive model with only a single clinical parameter (body mass index) improved predictive ability for development of AIS (AUROC = 0.722, net reclassification improvement [NRI] 0.505 ± 0.054, p = 1.6 × 10-8 ), potentiating clinical use of the prediction model. Furthermore, we found the Cobb angle (CA), the severity measurement of AIS, to be a polygenic trait that showed a significant genetic correlation with AIS susceptibility (rg = 0.6, p = 3.0 × 10-4 ). The AIS PRS demonstrated a significant association with CA. These results indicate a shared polygenic architecture between onset and progression of AIS and the potential usefulness of PRS in clinical settings as a predictor to promote early intervention of AIS and avoid invasive surgery. © 2021 American Society for Bone and Mineral Research (ASBMR).

Eight novel susceptibility loci and putative causal variants in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is the most common allergic disease in the world. While genetic components play critical roles in its pathophysiology, a large proportion of its genetic background is still unexplored. OBJECTIVES: This study sought to illuminate the genetic associations with AD using genome-wide association study (GWAS) and its downstream analyses. METHODS: This study conducted a GWAS for AD comprising 2,639 cases and 115,648 controls in the Japanese population, followed by a trans-ethnic meta-analysis with UK Biobank data and downstream analyses including partitioning heritability analysis by linkage disequilibrium score regression. RESULTS: This study identified 17 significant susceptibility loci, among which 4 loci-AFF1, ITGB8, EHMT1, and EGR2-were novel in the Japanese GWAS. The trans-ethnic meta-analysis revealed 4 additional novel loci, namely-ZBTB38,LOC105755953/LOC101928272, TRAF3, andIQGAP1. This study found a missense variant (R243W) with a deleterious functional effect in NLRP10 and a variant altering expression of CCDC80 via enhancer expression as highly likely causal variants. These 2 regions were Asian-specific, and these population-specific associations could be explained by the frequency of causal variants. The gene-based test showed SMAD4 as an additional novel significant locus. Downstream analyses revealed substantial overlap of GWAS significant signals in enhancers of skin cells and immune cells, especially CD4 T cells. A highly shared polygenic architecture of AD between Europeans and Asians was also found. CONCLUSIONS: This study identified Japanese-specific loci and novel significant loci shared by different populations. Two putative causal variants were illuminated in Japanese-specific loci. Trans-ethnic analyses revealed strong heritability enrichment in immune-related pathways, and relevant cell types shared among populations.

Genome-wide association study of epilepsy in a Japanese population identified an associated region at chromosome 12q24.

OBJECTIVE: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population. METHODS: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data. RESULTS: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10-10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24. SIGNIFICANCE: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.