Large-scale plasma proteomics comparisons through genetics and disease associations

Nature, Journal Year: 2023, Volume and Issue: 622(7982), P. 348 - 358

Published: Oct. 4, 2023

High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge gap between genome diseases. Here we performed association studies Olink Explore 3072 data generated by UK Biobank Pharma Proteomics Project

Language: Английский

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Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 1, 2024

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well clinical practice for diagnosis of neurological diseases, e.g., Alzheimer's disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence variability mean standardized protein levels. We show that these differences cause many commonly reported highly correlated, thereby producing misleading results if not accounted for. To adjust this variability, identified evaluated high-performing reference proteins which improved diagnostic accuracy key AD biomarkers. Our method attenuates risk false positive findings, improves sensitivity specificity biomarkers, with broad implications both practice.

Language: Английский

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Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: June 9, 2023

The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes disease-associated loci. QTL mapping mainly been focused on multi-tissue expression or plasma protein (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs which 1,585 are unique to CSF, demonstrating genetic regulation CSF proteome. In addition established chr6p22.2-21.32 HLA region, pleiotropic regions chr3q28 near

Language: Английский

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Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 7, 2024

Abstract Background Antibody-based immunoassays have enabled quantification of very low concentrations phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding the diagnosis AD. Mass spectrometry enables absolute multiple p-tau variants within a single run. The goal this study was to compare performance mass assessments 181 , 217 and 231 with established immunoassay techniques. Methods We measured CSF from 173 participants TRIAD cohort 394 BioFINDER-2 using both methods. All subjects were clinically evaluated by dementia specialists had amyloid-PET tau-PET assessments. Bland–Altman analyses agreement between . P-tau associations uptake also compared. Receiver Operating Characteristic (ROC) compared identify positivity. Results highly comparable terms diagnostic performance, between-group effect sizes PET biomarkers. In contrast, antibody-free lower immunoassays. Conclusions Our results suggest that while similar overall, immunoassay-based biomarkers are slightly superior spectrometry-based Future work is needed determine whether potential evaluate run offsets quantification.

Language: Английский

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Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer’s disease

Nature Human Behaviour, Journal Year: 2024, Volume and Issue: 8(10), P. 2047 - 2066

Published: July 10, 2024

Language: Английский

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Promises and Challenges of populational Proteomics in Health and Disease

Molecular & Cellular Proteomics, Journal Year: 2024, Volume and Issue: 23(7), P. 100786 - 100786

Published: May 17, 2024

Language: Английский

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Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(12), P. 2672 - 2684

Published: Nov. 11, 2024

Language: Английский

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Identification of potential therapeutic targets for Alzheimer's disease from the proteomes of plasma and cerebrospinal fluid in a multicenter Mendelian randomization study

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 294, P. 139394 - 139394

Published: Jan. 5, 2025

Language: Английский

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The genetic regulation of protein expression in cerebrospinal fluid

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 15(1)

Published: Dec. 12, 2022

Article12 December 2022Open Access Source DataTransparent process The genetic regulation of protein expression in cerebrospinal fluid Oskar Hansson Corresponding Author [email protected] orcid.org/0000-0001-8467-7286 Clinical Memory Research Unit, Faculty Medicine, Lund University, Lund, Sweden Clinic, Skåne University Hospital, Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Methodology, Project administration, Writing - review & editing Search for more papers by this author Atul Kumar orcid.org/0000-0002-2166-4805 Data curation, Software, Formal analysis, Visualization, Shorena Janelidze Erik Stomrud Philip S Insel Department Psychiatry and Behavioral Sciences, California, San Francisco, CA, USA Kaj Blennow orcid.org/0000-0002-1890-4193 Neurochemistry Laboratory, Sahlgrenska Mölndal, Neurochemistry, Institute Neuroscience Physiology, the Academy, Gothenburg, Henrik Zetterberg Neurodegenerative Disease, UCL Neurology, London, UK Dementia at UCL, Hong Kong Center Diseases, Kong, China Eric Fauman Internal Medicine Pfizer Worldwide Research, Development Medical, Cambridge, MA, Åsa K Hedman Stockholm, Medical Epidemiology Biostatistics, Karolinska Institutet, Michael W Nagle orcid.org/0000-0002-4677-7582 Neurogenomics, Genetics-Guided Discovery, Eisai, Inc, Christopher D Whelan Translational Biology, Biogen Development, Denis Baird Anders Mälarstig Niklas Mattsson-Carlgren orcid.org/0000-0002-8885-7724 Wallenberg Molecular Validation, original draft Information *,1,2, Kumar1, Janelidze1, Stomrud1,2, Insel1,3, Blennow4,5, Zetterberg4,5,6,7,8, Fauman9, Hedman10,11, Nagle12, Whelan13, Baird14, Mälarstig10,11 *,1,14,15 1Clinical 2Memory 3Department 4Clinical 5Department 6Department 7UK 8Hong 9Internal 10Pfizer 11Department 12Neurogenomics, 13Translational 14Department 15Wallenberg *Corresponding author. Tel: +46 040 331000; E-mail: 072 5759329; EMBO Mol Med (2023)15:e16359https://doi.org/10.15252/emmm.202216359 PDFDownload PDF article text main figures.PDF PLUSDownload text, figures, expanded view figures appendix. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Studies (CSF) proteins may reveal pathways treatment neurological diseases. 398 CSF were measured 1,591 participants from BioFINDER study. Protein quantitative trait loci (pQTL) identified as associations between variants proteins, with 176 pQTLs 145 (P < 1.25 × 10−10, 117 cis-pQTLs 59 trans-pQTLs). Ventricular volume (measured brain magnetic resonance imaging) was confounder several pQTLs. plasma overall correlated, but CSF-specific also observed. Mendelian randomization analyses suggested causal roles example, ApoE, CD33, GRN Alzheimer's disease, MMP-10 preclinical SIGLEC9 amyotrophic lateral sclerosis, CD38, GPNMB, ADAM15 Parkinson's disease. levels GRN, MMP-10, GPNMB altered respectively. These findings point be explored novel therapies. finding that ventricular confounded has implications design future studies proteome. Synopsis can increase understanding disease mechanisms. This study (pQTLs) analyzed highly specific extension assays large human population. significant identified, most which had not been described previously proteins. When combining results external GWAS data sources experiments, potential diseases, others. pQTL imaging (MRI), ventricle possible some Introduction Cerebrospinal is produced within rich source biomarkers correlate pathologies across different diseases (Hansson, 2021). While control proteome yield insights into mechanisms treatments, only few such have performed date on larger sets (Kunkle et al, 2019; Sasayama Yang 2021), or focused disease-associated (Deming 2017; Maxwell 2018). In contrast, blood consistently shown associated levels, known (pQTL), using both aptamer-based (Sun 2018; Ferkingstad 2021) antibody-based (Folkersen 2020) are common explain up 30% variance. Identification makes it test if likely development (hence nominating them candidate drug targets). For needed rather than identify targets. largest previous used an approach (Yang Recent comparisons aptamer- highlight technology quantification could impact findings, methods being (Katz 2022). Therefore, we attempted discover deeply phenotyped cohort healthy controls patients biomarker capture wide range biological pathways. We mainly proximity (PEA), sensitive (Assarsson 2014; Katz 2022), together selected other assays, orthogonal validation. evaluated (MRI) (due dilution effects) pQTLs, our knowledge done before studies. overarching aim map decipher clinically relevant expressed subsequently secreted CSF, focus general particular. Results Genome-wide analysis reveals independent Fig 1. total, included (53% females), mean age 71.3 (standard deviation 7.1) years. Most cognitively unimpaired (CU) individuals (613 normal 210 subjective cognitive decline [SCD]), remaining 280 mild impairment (MCI) patients, 189 (AD) dementia 155 (PD) 30 Parkinsons' (PDD) 21 progressive supranuclear palsy (PSP) 24 Lewy bodies (DLB) 14 vascular (VaD) 5 frontotemporal lobe (FTD) 27 multiple system atrophy (MSA) 6 corticobasal syndrome (CBS) 11 unspecified parkinsonism, (demographics diagnosis Table EV1). Figure Study flowchart A schematic overview design. Download figure PowerPoint There available (Dataset EV1) genome-wide 10.53 million (with imputation INFO score ≥ 0.6; MAF 1%). After correction Bonferroni method (genome-wide significance P 10−8 divided number tested 1.253 10−10 CSF), found among (Figs 2 EV1), (N = 117) trans-pQTLs 59). 197 141 N 56 trans-pQTLs), 153 Dataset EV2 (together all least [P 10−8] facilitate meta-analyses). distributed assay platforms (Appendix S1). minor allele frequencies inversely correlated effect size (Fig 3A), strengths cis-pQTL decreased longer distance transcription start sites 3B). functional annotation 3C) enrichment (after over categories) intronic (49% vs. 36% reference panel), exonic (1.8% 1.0%), downstream (1.7% 1.1%) variants, while intergenic (35% 47%) ncRNA-intronic (8.9% 11.5%) significantly less common. 2. genomic Each represents protein. sizes bubbles proportional β-coefficient effects. An interactive version plot EV1. 3. mapping Relationships (β) frequency (MAF) indicated (only after included). cis-pQTLs, degree site (TSS). interquartile −37.3 0.12 Kb. annotated. Functional generated FUMA, correction. Enrichment consequences SNPs against European 1,000 genome panel. Asterixes indicate differences proportions versus panel (***P 0.001; *P 0.05). Click here expand figure. Interactive pQTLsThis Full functionality provided file "Fig EV1 CSF_pQTL_interactive.html", online. online adjusted diagnostic group, sensitivity repeated subgroup controls, similar S2). three measures PEA additional (Meso Scale Discovery CCL2 CCL4, ELISA CHI3L1), validated alternative EV2; EV2, lines marked yellow). Our annotate genes distance, through chromatin interaction yielded largely overlapping EV2). EV2. A–D. Between-assay correlations OLINK (proximity assay) methods, four where (panel A: CHI3L1, B: CCL2, C: D: NFL). manuscript. (using labels assays: MCP1 MIP1b YKL-40 rows same variant (rs2228467, trans-pQTL) assays. one (rs113341849) (rs879571071) LD (rs8064426, R2 0.200, D′ 0.687). (rs4950928), high (rs946262, 0.902, 1.0). these cases, similar, stable direction general, (Spearman Rho 0.69, 0.001, EV3). However, out 162 matching plasma, there 74 (46%) (44 43 trans-pQTLs, 39 putative genes) non-significant even level > 10−8) plasma. One example IL-6, (rs79103996) 2.9 10−29) no association 0.38), suggesting tissue-specificity IL-6 regulation. testing tissue two enriched cerebral cortex (OSTN, 34 DRAXIN, 1 cis-pQTL). EV3. plasmaThe shows relationship 5e-8) CSF. differed tissues, CXCL1, lower higher Genetic variant-to-protein specificity Among correction) 140 unique locus, predominantly acting cis 4A, see Appendix S3 pQTLs), trans-acting (for loci, strongest nominated carried further analyses), six CCL4 (two RBKS (all cis-pQTLs), each CCL24 CTSS LRPAP1 Conversely, 4B). notable exception region represented rs71635338 chromosome 3, (see below detailed analysis). noted rs429358 cis-pQTLs). defines APOE genotype, well-known related (AD), (lower Aβ42, T-tau P-tau (Chung 2018)). 4. Overview architecture Number per A), top B). Validation queried EBI-GWAS catalog (September 2022) study, Methods section. Novelty assessed depending whether any prior observed locus. result novelty assessment full hits EV4. Detailed CNS Datasets EV5 EV6, summary, pQTL-protein pairs 19 (10.9%) publications (the reported 82 (47.1%) serum (24.7%) protein, locus (15.5%) 3 (1.7%) completely (no tissue). Another recently published proteomics 971 samples, 275 applied panels overlapped 235 conducted head-to-head comparison results. Fifteen replicated (significant effects respect risk allele) EV4; EV7). Out 15, 12 cis-acting trans-acting. Further, 8 proxy match (up 10 kb) al (2021) directionality studies). (rs76904798) (2021). second (rs12126142) (PSME1) (IL6R). eight (including proteins) studies, reversed part Replication (2021)This current another recent publication EV4 pQTLs.html", Matching co-localization eQTLs To understand mechanism influence investigated mRNA gene expression. All eQTL meta-analysis (Sieberts GTEx database (restricting search tissues), P-value 0.05 (false discovery rate [FDR]-adjusted) denote statistical significance. comparing 53 showed

Language: Английский

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Identification of cerebral spinal fluid protein biomarkers in Niemann-Pick disease, type C1

Biomarker Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: Jan. 31, 2023

Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype heterogeneous with variable age of onset, classical a pediatric disorder. Currently there are no therapies approved FDA therapeutics trials for complicated rarity, heterogeneity, relatively slow rate neurological decline. Thus, identification relevant biomarkers necessary to provide tools that can support drug development efforts this devastating disease. Proximal extension assays (O-link® Explore 1536) were used compare cerebrospinal fluid (CSF) samples from individuals enrolled in natural history study non-NPC1 comparison samples. Relative expression levels 1467 proteins determined, candidate protein identified evaluating fold-change adjusted Kruskal-Wallis test p-values. Selected orthogonally confirmed using ELISA. To gain insight into progression severity we evaluated altered respect clinically phenotypic aspects: NPC Neurological Severity Score (NPC1 NSS), Annual Increment (ASIS) onset. This multiple CSF compared These included previously shown be elevated (NEFL, MAPT, CHIT1, CALB1) additional orthogonal (PARK7, CALB2/calretinin, CHI3L1/YKL-40, MIF, CCL18 ENO2). Correlations parameters demonstrated moderate negative (p = 0.0210, r -0.41) possible positive 0.0631, 0.33) correlation CALB2 onset ASIS, respectively. CHI3L1 showed 0.0183, 0.40) concurrent NSS. A strong 0.0016, -0.648) was observed between childhood/adolescent cases. also 0.0017, 0.61) ASIS. Our validated candidates further investigation larger cohort. analytes may prove useful as supportive data therapeutic trials. NCT00344331, NCT00001721, NCT02931682.

Language: Английский

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