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Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.
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http://dx.doi.org/10.1093/hmg/ddq571 | DOI Listing |
Unlabelled: The corticospinal tract (CST) facilitates skilled, precise movements, which necessitates that subcerebral projection neurons (SCPN) establish segmentally specific connectivity with brainstem and spinal circuits. Developmental molecular delineation enables prospective identification of corticospinal neurons (CSN) projecting to thoraco-lumbar spinal segments; however, it remains unclear whether other SCPN subpopulations in developing sensorimotor cortex can be prospectively identified in this manner. Such molecular tools could enable investigations of SCPN circuitry with precision and specificity.
View Article and Find Full Text PDFDev Cell
December 2024
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA 94303, USA. Electronic address:
Critical molecular pathways promote central nervous system (CNS) axon regeneration, but can axons be guided to their correct targets in adulthood? In this issue of Developmental Cell, Delpech et al. show that axonal guidance cues in the CNS can be manipulated to enhance anatomic and functional recovery.
View Article and Find Full Text PDFMed Image Anal
December 2024
School of Automation, Northwestern Polytechnic University, Xi'an, 710072, China. Electronic address:
A deep comparative analysis of brain functional connectome across species in primates has the potential to yield valuable insights for both scientific and clinical applications. However, the interspecies commonality and differences are inherently entangled with each other and with other irrelevant factors. Here we develop a novel contrastive machine learning method, called shared-unique variation autoencoder (SU-VAE), to allow disentanglement of the species-shared and species-specific functional connectome variation between macaque and human brains on large-scale resting-state fMRI datasets.
View Article and Find Full Text PDFComp Biochem Physiol Part D Genomics Proteomics
December 2024
Institute of Animal Husbandry and Veterinary, Tibet Autonomous Regional Academy of Agricultural Sciences, Lhasa, Tibet 850000, China. Electronic address:
Yak meat plays a significant economic role for yaks. The unique environment of the Qinghai-Tibet plateau profoundly impacts the meat production performance of yaks. Yet, the regulatory mechanisms influencing muscle growth and development in yaks within this plateau environment remain poorly understood.
View Article and Find Full Text PDFFront Mol Neurosci
December 2024
State Key Laboratory of Optometry, Ophthalmology and Vision Science, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Neuronal radial migration is a fundamental process for cortical development, the disruption of which causes neurological and psychiatric dysfunctions. SLIT2 plays diverse functions in brain development and is a well-known axon guidance molecule. In this study, we investigated the radial migration of projection neurons in the developing cerebral cortex by knockdown (KD) of in mice.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!