745 research outputs found
Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes
No full textAbstract: Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 x 10(-8)) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis
Copy number variation and haplotype analysis of 17q21.31 reveals increased risk associated with progressive supranuclear palsy and gene expression changes in neuronal cells
No full textAbstract: Background: The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). Objective: To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. Methods Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (alpha, beta, and gamma) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. Results: We found that the copy number of gamma was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1 beta 1 gamma 1 (OR = 1.21) and H1 beta 2 gamma 1 (OR = 1.24) to H1 beta 1 gamma 4 (OR = 1.57), structural forms of H1 with additional copies of gamma displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two gamma copies to 88% in those with eight copies. Additionally, gamma duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals gamma duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. Conclusions: The copy number of gamma is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. (c) 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
No full textAbstract: BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE epsilon 2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 x 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions
Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
No full textAbstract: Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer\u2019s disease (AD), we observed the APOE \u3b52 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73
710-3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions
Fast identification of biological pathways associated with a quantitative trait using group lasso with overlaps.
No full textWhere causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways.We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our "pathways group lasso with adaptive weights" (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets.In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
No full textGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10<sup>−11</sup>; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes
Spatially structured genetic variation in a broadcast spawning bivalve: quantitative vs. molecular traits
No full textUnderstanding the origin, maintenance and significance of phenotypic variation is one of the central issues in evolutionary biology. An ongoing discussion focuses on the relative roles of isolation and selection as being at the heart of genetically based spatial variation. We address this issue in a representative of a taxon group in which isolation is unlikely: a marine broadcast spawning invertebrate. During the free-swimming larval phase, dispersal is potentially very large. For such taxa, small-scale population genetic structuring in neutral molecular markers tends to be limited, conform expectations. Small-scale differentiation of selective traits is expected to be hindered by the putatively high gene flow. We determined the geographical distribution of molecular markers and of variation in a shell shape measure, globosity, for the bivalve Macoma balthica (L.) in the western Dutch Wadden Sea and adjacent North Sea in three subsequent years, and found that shells of this clam are more globose in the Wadden Sea. By rearing clams in a common garden in the laboratory starting from the gamete phase, we show that the ecotypes are genetically different; heritability is estimated at 23%. The proportion of total genetic variation that is between sites is much larger for the morphological additive genetic variation (QST = 0.416) than for allozyme (FST = 0.000–0.022) and mitochondrial DNA cytochrome-c-oxidase-1 sequence variation (ΦST = 0.017). Divergent selection must be involved and intraspecific spatial genetic differentiation in marine broadcast spawners is apparently not constrained by low levels of isolation.
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
No full textUsing the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals
Publisher correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes(Nature Genetics, (2018) 50, 4, (524-537), 10.1038/s41588-018-0058-3)
No full text© 2019, Nature Publishing Group. All rights reserved. In the HTML version of this article initially published, the author groups ‘AFGen Consortium’, ‘Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium’, ‘International Genomics of Blood Pressure (iGEN-BP) Consortium’, ‘INVENT Consortium’, ‘STARNET’, ‘BioBank Japan Cooperative Hospital Group’, ‘COMPASS Consortium’, ‘EPIC-CVD Consortium’, ‘EPIC-InterAct Consortium’, ‘International Stroke Genetics Consortium (ISGC)’, ‘METASTROKE Consortium’, ‘Neurology Working Group of the CHARGE Consortium’, ‘NINDS Stroke Genetics Network (SiGN)’, ‘UK Young Lacunar DNA Study’ and ‘MEGASTROKE Consortium’ appeared at the end of the author list but should have appeared earlier in the list. In addition, the author group ‘MEGASTROKE Consortium’ was duplicated, and its members were not displayed in the ‘Author information’ section. The errors have been corrected in the HTML version of the article
Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
No full textCorrection to: Nature Genetics https://doi.org/10.1038/s41588-021-01007-6, published online 24 February 2022
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