Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong ...genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.
The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we ...comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations (P < 7.45 × 10
) across the allele frequency spectrum, all of which replicate in an independent cohort (n = 1605, 18.4x WGS). We identify for the first time replicating evidence for rare-variant cis-acting protein quantitative trait loci for five genes, involving both coding and noncoding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets.
Gene and protein expression profiles of iris biopsies, aqueous humor (AqH), and sera in patients with juvenile idiopathic arthritis-associated uveitis (JIAU) in comparison to control patients with ...primary open-angle glaucoma (POAG) and HLA-B27-positive acute anterior uveitis (AAU) were investigated. Via RNA Sequencing (RNA-Seq) and mass spectrometry-based protein expression analyses 136 genes and 56 proteins could be identified as being significantly differentially expressed (DE) between the JIAU and POAG group. Gene expression of different immunoglobulin (Ig) components as well as of the B cell-associated factors ID3, ID1, and EBF1 was significantly upregulated in the JIAU group as compared to POAG patients. qRT-PCR analysis showed a significantly higher gene expression of the B cell-related genes CD19, CD20, CD27, CD138, and MZB1 in the JIAU group. At the protein level, a significantly higher expression of Ig components in JIAU than in POAG was confirmed. The B cell-associated protein MZB1 showed a higher expression in JIAU patients than in POAG which was confirmed by western blot analysis. Using bead-based immunoassay analysis we were able to detect a significantly higher concentration of the B cell-activating and survival factors BAFF, APRIL, and IL-6 in the AqH of JIAU and AAU patients than in POAG patients. The intraocularly upregulated B cell-specific genes and proteins in iris tissue suggest that B cells participate in the immunopathology of JIAU. The intracameral environment in JIAU may facilitate local effector and survival functions of B cells, leading to disease course typical for anterior uveitis.
•Iris of juvenile idiopathic arthritis-associated uveitis (JIAU) is characterized by distinct gene and protein expression.•Gene and proteome expression point to presence and longevity of B cells and plasma cells in the iris of JIAU patients.•Elevated BAFF and APRIL concentrations in aqueous humor of JIA-uveitis may contribute to longevity of B and plasma cells.
Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure ...for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein
as a novel potential target.
is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for
in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as
for further translational investigation.
We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and ...metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10.sup.-6) and ADAMTS12 (rs1364044, p = 2.9x10.sup.-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10.sup.-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a ...GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P < 10−5). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (SMAP1), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and β-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of P = 1.42 × 10−6/2.0 × 10−6 and P = 6.11 × 10−6/1.8 × 10−5, respectively. Rs2748331 was replicated (P = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined P = 7.88 × 10−7). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in SMAP1 and 3 in RIMS1, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: P = .08326, SMAP1; rs767118962: P = .08326, RIMS1; and rs41265501: P = .05778, RIMS1). In conjunction, our data provide compelling evidence for SMAP1, B3GAT2, and RIMS1 as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.
•Our study identified a region on chromosome 6 comprising the genes SMAP1, B3GAT2, and RIMS1 as novel susceptibility locus for pediatric VTE.•Nonsynonymous variants in SMAP1 and RIMS1 are predicted as deleterious and may influence vesicle processing in blood cells.
Deep sequencing offers unparalleled access to rare variants in human populations. Understanding their role in disease is a priority, yet prohibitive sequencing costs mean that many cohorts lack the ...sample size to discover these effects on their own. Meta-analysis of individual variant scores allows the combination of rare variants across cohorts and study of their aggregated effect at the gene level, boosting discovery power. However, the methods involved have largely not been field-tested. In this study, we aim to perform the first meta-analysis of gene-based rare variant aggregation optimal tests, applied to the human cardiometabolic proteome.
Here, we carry out this analysis across MANOLIS, Pomak and ORCADES, three isolated European cohorts with whole-genome sequencing (total N = 4,422). We examine the genetic architecture of 250 proteomic traits of cardiometabolic relevance. We use a containerised pipeline to harmonise variant lists across cohorts and define four sets of qualifying variants. For every gene, we interrogate protein-damaging variants, exonic variants, exonic and regulatory variants, and regulatory only variants, using the CADD and Eigen scores to weigh variants according to their predicted functional consequence. We perform single-cohort rare variant analysis and meta-analyse variant scores using the SMMAT package.
We describe 5 rare variant pQTLs (RV-pQTL) which pass our stringent significance threshold (7.45 × 10−11) and quality control procedure. These were split between four cis signals for MARCO, TEK, MMP2 and MPO, and one trans association for GDF2 in the SERPINA11 gene. We show that the cis-MPO association, which was not detectable using the single-point data alone, is driven by 5 missense and frameshift variants. These include rs140636390 and rs119468010, which are specific to MANOLIS and ORCADES, respectively. We show how this kind of signal could improve the predictive accuracy of genetic factors in common complex disease such as stroke and cardiovascular disease.
Our proof-of-concept study demonstrates the power of gene-based meta-analyses for discovering disease-relevant associations complementing common-variant signals by incorporating population-specific rare variation.
•Meta-analysis of gene-based variant scores leverages population-specific allelic heterogeneity.•We study rare variants influencing 250 circulating serum proteins in two Greek population isolates.•4 cis and 1 trans coding variant signals are study-wide significant and pass quality control.•Five rare coding variants influence protein expression of myeloperoxidase (MPO).•Different isolates are enriched for different rare coding MPO variants.
Recently, we reported a gene network of ADAMTS (A Disintegrin-like and Metalloprotease with Thrombospondin motifs) genes as central component of the genetic risk contributing to pediatric stroke. ...ADAMTS13 is a prime example for such a key component as it cleaves von Willebrand factor multimers, reduces platelet adhesion and aggregation, and downregulates thrombus formation and inflammation.
We characterized the genetic architecture of ADAMTS13 through targeted next-generation sequencing of 48 affected children and their unaffected siblings and identified in total 241 variants (single nucleotide polymorphisms or insertions/deletions) in the ADAMTS13 gene. From these, based on significance in the sibship disequilibrium test (P<0.05) or protein-altering properties, we selected 21 common variants covering the complete ADAMTS13 gene for genotyping in 270 trios and subsequent association analyses. Transmission disequilibrium testing was performed for affection status and ADAMTS13 activity levels using PLINK and FBAT, respectively. Ten single nucleotide polymorphisms were significantly associated with pediatric stroke (P<0.05 to P<0.001), 2 of which (rs2285489 and rs28793911) were also significantly associated with ADAMTS13 levels (P=0.0004 and P=0.0092). The resulting protective haplotype H1.1. (T:U 95.5: 144.4; P=0.0016) is associated with increased ADAMTS13 levels (age-adjusted P=0.0108). Haplotype association using a sliding window approach assigns this association to the ADAMTS13 von Willebrand factor-binding domain (P=1.2×10(-4)).
Our data provide a link between the genetic architecture of ADAMTS13, ADAMTS13 levels, and stroke susceptibility. Altogether, these studies render ADAMTS13 an attractive candidate for functional studies and may contribute to personalized diagnosis and treatment options in future.
The stimulator of interferon genes (STING) protein bridges sensors of cytosolic DNA and the inflammatory pathway mediated by interferon-β. Activating mutations in the
STING
gene cause a vascular and ...pulmonary syndrome.
Studies involving children with monogenic autoinflammatory disease have provided insights into the regulation of key proinflammatory cytokine pathways and their role in causing systemic and organ-specific inflammation.
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We studied six patients who presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks, and ears that progressed to acral necrosis in most of the patients and did not respond to therapy. A mixed histologic pattern was observed, consisting of a prominent dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels. Three of the patients had severe interstitial lung . . .
Abstract
Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically determined regulation of proteins that are ...dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 248 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analyzing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5× WGS) and Pomak (n = 1537; 18.4× WGS), we detect 301 independently associated pQTL variants for 170 proteins, including 12 rare variants (minor allele frequency < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations but have drifted up in the frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including Mep1b for high-density lipoprotein (HDL) levels, and describe a knock-out (KO) Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein–disease relationships and demonstrate the importance of isolated populations in pQTL analysis.
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