Identification of LRRC46 as a novel candidate gene for high myopia

High myopia(HM)is the primary cause of blindness,with the microstructural organization and composition of collagenous fibers in the cornea and sclera playing a crucial role in the biomechanical behavior of these tissues.In a previously reported myopic linkage region,MYP5(17q21-22),a potential candidate gene,LRRC46(c.C235T,p.Q79X),was identified in a large Han Chinese pedigree.LRRC46 is expressed in various eye tissues in humans and mice,including the retina,cornea,and sclera.In subsequent cell experiments,the mutation(c.C235T)decreased the expression of LRRC46 protein in human corneal epithelial cells(HCE-T).Further investigation revealed that Lrrc46^(-/-)mice(KO)exhibited a classical myopia phenotype.The thickness of the cornea and sclera in KO mice became thinner and more pronounced with age,the activity of limbal stem cells decreased,and microstructural changes were observed in the fibroblasts of the sclera and cornea.We performed RNA-seq on scleral and corneal tissues of KO and normal control wild-type(WT)mice,which indicated a significant downregulation of the collagen synthesis-related pathway(extracellular matrix,ECM)in KO mice.Subsequent in vitro studies further indicated that LRRC46,a member of the important LRR protein family,primarily affected the formation of collagens.This study suggested that LRRC46 is a novel candidate gene for HM,influencing collagen protein VⅢ(Col8a1)formation in the eye and gradually altering the biomechanical structure of the cornea and sclera,thereby promoting the occurrence and development of HM.

Association analysis of genetic variants in critical patients with COVID-19 and validation in a Chinese population

Dear Editor,Genome-wide association studies(GWASs)have reported a genetic association between certain populations and the severity of COVID-19.In severe patients,changes in the locus 3p21.31(including SLC6A20,LZTFL1,CCR9,FYCO1,CXCR6,and XCR1)are associated with COVID-19 hospitalization(Ellinghaus et al.,2020).Moreover,variations in 9p34.2 region(including genes related to the ABO blood grouping)can affect both susceptibility and severity of COVID-19;in particular,individuals with blood group A may have an increased risk of COVID-19 infection,while those with blood group O may have a protective effect(Ellinghaus et al.,2020;Shelton et al.,2021).

Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy

Age-related macular degeneration (AMD) is a complex eye disorder and is the leading cause of incurable blindness worldwide in the elderly. Clinically, AMD initially affects the central area of retina known as the macula and it is classified as early stage to late stage (advanced AMD). The advanced AMD is classified into the nonexudative or atrophic form (dry AMD) and the exudative or neovascular form (wet AMD). More severe vision loss is typically associated with the wet form. Multiple genetic factors, lipid metabolism, oxidative stress and aging, play a role in the etiology of AMD. Dysregulation in genetic to AMD is established to 46%–71% of disease contribution, with CFH and ARMS2/HTRA1 to be the two most notable risk loci among the 103 identified AMD associated loci so far. Chronic cigarette smoking is the most proven consistently risk living habits for AMD. Deep learning algorithm has been developed based on image recognition to distinguish wet AMD and normal macula with high accuracy. Currently, anti-vascular endothelial growth factor (VEGF) therapy is highly effective at treating wet AMD. Several new generation AMD drugs and iPSC-derived RPE cell therapy are in the clinical trial stage and are promising to improve AMD treatment in the near future.

Detection of serum IgM and IgG for COVID-19 diagnosis

Dear Editor,Infection with the novel coronavirus(SARS-CoV-2,which is the virus responsible for the coronavirus disease 2019(COVID-19))was first reported in Wuhan,China on December 31,2019.The outbreak of COVID-19 remains ongoing and was linked to more than 80,000 infected patients and more than 3,000 deaths in China as of March 7,2020(Holshue et al.,2020).

Dynamic blood single-cell immune responses in patients with COVID-19

The 2019 coronavirus disease(COVID-19)outbreak caused by the SARS-CoV-2 virus is an ongoing global health emergency.However,the virus'pathogenesis remains unclear,and there is no cure for the disease.We investigated the dynamic changes of blood immune response in patients with COVID-19 at different stages by using 5'gene expression,T cell receptor(TCR),and B cell receptors(BCR)V(D)J transcriptome analysis at a single-cell resolution.We obtained single-cell mRNA sequencing(scRNA-seq)data of 341,420 peripheral blood mononuclear cells(PBMCs)and 185,430 donotypic T cells and 28,802 donotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies.In addition,we used three control samples.We found expansion of dendritic cells(DCs),CD14+monocytes,and megakaryocytes progenitor cells(MP)/platelets and a reduction of naive CD4+T lymphocytes in patients with COVID-19,along with a significant decrease of CD8+T lymphocytes,and natural killer cells(NKs)in patients in critical condition.The type I interferon(IFN-I),mitogen-activated protein kinase(MAPK),and ferroptosis pathways were activated while the disease was active,and recovered gradually after patient conditions improved.Consistent with this finding,the mRNA level of IFN-I signal-induced gene IFI27 was significantly increased in patients with COVID-19 compared with that of the controls in a validation cohort that included 38 patients and 35 controls.The concentration of interferon-a(IFN-a)in the serum of patients with COVID-19 increased significantly compared with that of the controls in an additional cohort of 215 patients with COVID-19 and 106 controls,further suggesting the important role of the IFN-I pathway in the immune response of COVID-19.TCR and BCR sequences analyses indicated that patients with COVID-19 developed specific immune responses against SARS-CoV-2 antigens.Our study reveals a dynamic landscape of human blood immune responses to SARS-CoV-2 infection,providing clues for therapeutic potentials in treating COVID-19.

Genome-wide analysis identified 17 new loci influencing intraocular pressure in Chinese population

Intraocular pressure(IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10^(-7), and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10^(-8), including 4 previously reported loci: rs145063132(7 p21.2, ETV1/DGKB), rs548030386(7 q31.2, ST7 near CAV1/CAV2), rs7047871(9 p24.2, GLIS3), and rs2472494(9 q31.1, ABCA1/SLC44 A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2(rs7525308 in 1 p34.1), LRIF1/DRAM2(rs1282146 in 1 p13.3), COLEC11(rs201143466 in 2 p25.3),SPTBN1(rs4514918 in 2 p16.2), and CRK(rs11078446 in 17 p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.

Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's disease

Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular networks in a CAG length genotype-and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats.Furthermore,a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats.However,an integrated analysis correlating phenotype features with genotypes(CAG repeat expansions)was not conducted previously.In this study,we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples,together with behavioral features(396 PhenoCube behaviors and 111 NeuroCube behaviors)in Htt CAG-knock-in mice.We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration.The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions,which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain.We also identified 15 chemicals with significant responses for genes with enriched behavioral features,most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry.Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.

Dynamic human retinal pigment epithelium(RPE)and choroid architecture based on single-cell transcriptomic landscape analysis

The retinal pigment epithelium(RPE)and choroid are located behind the human retina and have multiple functions in the human visual system.Knowledge of the RPE and choroid cells and their gene expression profiles are fundamental for understanding retinal disease mechanisms and therapeutic strategies.Here,we sequenced the RNA of about 0.3 million single cells from human RPE and choroids across two regions and seven ages,revealing regional and age differences within the human RPE and choroid.Cell–cell interactions highlight the broad connectivity networks between the RPE and different choroid cell types.Moreover,the transcription factors and their target genes change during aging.The coding of somatic variations increases during aging in the human RPE and choroid at the single-cell level.Moreover,we identified ELN as a candidate for improving RPE degeneration and choroidal structure during aging.The mapping of the molecular architecture of the human RPE and choroid improves our understanding of the human vision support system and offers potential insights into the intervention targets for retinal diseases.

Deep Sc-RNA sequencing decoding the molecular dynamic architecture of the human retina

The human retina serves as a light detector and signals transmission tissue.Advanced insights into retinal disease mechanisms and therapeutic strategies require a deep understanding of healthy retina molecular events.Here,we sequenced the m RNA of over 0.6 million single cells from human retinas across six regions at nine different ages.Sixty cell sub-types have been identified from the human mature retinas with unique markers.We revealed regional and age differences of gene expression profiles within the human retina.Cell-cell interaction analysis indicated a rich synaptic connection within the retinal cells.Gene expression regulon analysis revealed the specific expression of transcription factors and their regulated genes in human retina cell types.Some of the gene’s expression,such as DKK3,are elevated in aged retinas.A further functional investigation suggested that over expression of DKK3 could impact mitochondrial stability.Overall,decoding the molecular dynamic architecture of the human retina improves our understanding of the vision system.

Variants in the Wnt co-receptor LRP6 are associated with familial exudative vitreoretinopathy

Familial exudative vitreoretinopathy(FEVR),an inherited eye disease,is characterized by abnormal retinal vascular development,such as neovascularization,vitreous hemorrhage,exudation,and retinal detachment(Criswick and Schepens,1969;Robitaille et al.,2002).FEVR is inherited as autosomal dominant,autosomal recessive,and X-linked patterns(de Crecchio et al.,1998).

Whole exome sequencing identifies mutations of multiple genes in a Chinese cohort of 95 sporadic probands with presumptive retinitis pigmentosa

Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.

A genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19

Critical coronavirus disease 2019(COVID-19)is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19.We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19.632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited.First,we identified a genome-wide significant difference of IL-6 rs2069837(p=9.73×10^(−15),OR=0.41)between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort.