Biology subjects

Choquet, H.

Publications and source records attributed to Choquet, H..

5 recordsLinked to original sources

bioRxiv2026

PRSS56 acts as an intrinsic retinal signal driving postnatal ocular axial growth and myopia susceptibility

Myopia is a leading cause of visual impairment worldwide, and high myopia markedly increases the risk of irreversible vision loss. Although visual experience guides postnatal ocular elongation, the role of intrinsic retinal growth signals remains poorly defined. Here we identify the serine protease PRSS56 as a retinal factor that promotes ocular axial growth beyond early development. Using genetic mouse models, we show that conditional inactivation of Prss56 in Muller glia reduces axial length and causes hyperopia even under dark-rearing conditions, demonstrating that PRSS56 drives axial elongation independently of light-evoked visual input during emmetropization. Conversely, Muller glia-specific overexpression of Prss56 induces axial elongation in a proteolysis-dependent manner, supporting its role as an autonomous retinal growth signal. In concordance, human genetic analyses reveal that the common PRSS56 variant rs2853447 is associated with increased axial length in individuals with myopia and high myopia, but not in non-myopes, suggesting that this variant confers a selective growth advantage in individuals predisposed to ocular elongation. Functional genomic analyses further identify a myopia-associated variant, rs2741297, within a retinal enhancer in intron 4 of PRSS56 marked by open chromatin and transcription factor occupancy. Together, these findings establish PRSS56 as an intrinsic retinal growth factor that functions beyond early eye development and support a model in which genetic and environmental factors converge on retinal pathways to modulate myopia susceptibility.

genetics↗

bioRxiv2022

ADGRG6 promotes adipogenesis and is involved in sex-specific fat distribution

Fat distribution differences between males and females are a major risk factor for metabolic disease, but their genetic etiology remains largely unknown. Here, we establish ADGRG6 as a major factor in adipogenesis and gender fat distribution. Deletion of ADGRG6 in human adipocytes impairs adipogenesis due to reduced cAMP signaling. Conditionally knocking out Adgrg6 in mouse adipocytes or deleting an intronic enhancer associated with gender fat distribution generates males with female-like fat deposition, which are protected against high-fat-diet-induced obesity and have improved insulin response. To showcase its therapeutic potential, we demonstrate that CRISPRi targeting of the Adgrg6 promoter or enhancer prevents high-fat-diet-induced obesity. Combined, our results associate ADGRG6 as a gender fat distribution gene and highlight its potential as a therapeutic target for metabolic disease.

genomics↗

bioRxiv2021

GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open- angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Kruppel- like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P=4.73x10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

molecular biology↗

bioRxiv2021

A large-scale transcriptome-wide association study (TWAS) of ten blood cell phenotypes reveals complexities of TWAS fine-mapping

Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases. Hematological measures are highly heritable, and although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) using PrediXcan to systematically investigate the association between genetically-predicted gene expression and hematological measures in 54,542 individuals of European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We found 239 significant gene-trait associations with hematological measures. Among this set of 239 associations, we replicated 71 at p < 0.05 with same direction of effect for the blood cell trait in a meta-analysis of TWAS results consisting of up to 35,900 European ancestry individuals from the Womens Health Initiative (WHI), the Atherosclerosis Risk in Communities Study (ARIC), and BioMe Biobank. We further attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with these hematological measures, and performed further fine-mapping of TWAS loci. To assist with the interpretation of TWAS findings, we designed an R Shiny application to interactively visualize TWAS results, one genomic locus at a time, by integrating our TWAS results with additional genetic data sources (GWAS, TWAS from other gene expression reference panels, conditional analyses, known GWAS variants, etc.). Our results and R Shiny application highlight frequently overlooked challenges with TWAS and illustrate the complexity of TWAS fine-mapping efforts. Author SummaryTranscriptome-wide association studies (TWAS) have shown great promise in furthering our understanding of the genetic regulatory mechanisms underlying complex trait variation. However, interpreting TWAS results can be incredibly complex, especially in large-scale analyses where hundreds of signals appear throughout the genome, with multiple genes often identified in a single chromosomal region. Our research demonstrates this complexity through real data examples from our analysis of hematological traits, and we provide a useful web application to visualize TWAS results in a broadly approachable format. Together, our results and web application illustrate the importance of interpreting TWAS studies in context and highlight the need to carefully examine results in a region-wide context to draw reasonable conclusions and formulate mechanistic hypotheses.

genetics↗

bioRxiv2020

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer's disease

We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimers disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.

genetics↗