The genetic regulation of protein expression in cerebrospinal fluid

Hansson, Oskar; Kumar, Atul; Bateman, Randall J.; Stomrud, Erik; Insel, Philip S.; Blennow, Kaj; Zetterberg, Henrik; Fauman, Eric B.; Hedman, Åsa K.; Nagle, Michael W.; Whelan, Christopher D.; Baird, Denis; Mälarstig, Anders; Mattsson‐Carlgren, Niklas

doi:10.15252/emmm.202216359

Cited by 27 publications

(18 citation statements)

References 63 publications

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“…In our AD EA TWAS, we also identified genes associated with other neurological and autoimmune diseases including Parkinson’s disease ( CYB561 (68) and SLC25A39 (69)), Crohn’s disease ( ATG16L1 (70)), Amyotrophic lateral sclerosis ( SIGLEC9 (71)), and Riboflavin Transport Deficiency ( SLC52A1 (72)). These diseases have in common the progressive peripheral and cranial degeneration of neurons that impact processes such as voluntary muscle movement, vision, hearing and sensation.…”

Section: Discussionmentioning

confidence: 98%

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Chaar,

Li,

Shang

et al. 2024

Preprint

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Genetic variants increase the risk of neurocognitive disorders in later life including Vascular Dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiology are not well understood. Transcriptome-wide association studies (TWAS) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWAS have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European (EA) and African ancestries (AA) to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha=P<2.9−10-6), some of which were previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, downregulation ofICA1Lwas associated with higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS of cognitive function and neurocognitive disorders that used expression mapping studies in multiple ancestries. This work may expand the benefits of TWAS studies beyond a single ancestry group and help to identify gene targets for pharmaceutical or preventative treatment for dementia.Author SummaryTranscriptome-wide association studies (TWAS) can be used to understand the mechanisms of gene expression that underly disease etiology. However, to date, TWAS methods have mostly been used in a single ancestry group, especially European ancestry (EA), and few TWAS have focused on cognitive function or structural brain measures. We used a newly developed TWAS method called the Multi-ancEstry TRanscriptOme-wide analysis (METRO) to incorproate gene expression data from 801 EA and 1,032 African ancestry (AA) adults to identify genes associated with general cognitive function, structural brain changes called white matter hyperintensities (WMH) that predispose people to vascular dementia, and another form of dementia called Alzheimer’s disease (AD). We found that reduced gene expression ofICA1Lwas associated with more WMH and with AD, indicating its potential contribution to overlapping AD and vascular dementia neuropathologies. To our knowledge, our study is the first TWAS of cognitive function and neurocognitive disorders using multiple ancestries. This work may expand the benefits of TWAS studies beyond a single ancestry group and help to identify gene targets for pharmaceutical or preventative treatment for dementia.

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Section: Discussionmentioning

confidence: 98%

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Chaar,

Li,

Shang

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Despite not discovering additional supportive evidence for SIGLEC9 from either CSF database, a recent BioFINDER study involving 1,591 participants applied different CSF protein panels from Yang et al implicated shared effects of SIGLEC9 pQTL (rs2258983) with ALS. 41 In addition, owing to the close relationship between SIGLEC9 and SIGLEC7 (sharing 98% amino acid sequence similarity with the similar expression across immune cells and ligand affinity) 42 , both of these proteins warrant further investigations on their potential in ALS druggability.…”

Section: Discussionmentioning

confidence: 99%

Prioritization of therapeutic targets for amyotrophic lateral sclerosis using protein-wide Mendelian randomization analysis

Geng,

Chen,

Yang

et al. 2023

Preprint

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Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease with an increasing global burden. Available treatments for ALS present marginal efficacy. To identify novel candidate therapeutic targets for ALS, we conducted a proteome-wide Mendelian randomization (MR) study.MethodsWe leveraged data from the largest summary statistics for ALS to date (27,205 patients with ALS and 110,881 controls). Genetic instruments of more than 4,000 proteins defined bycis-protein quantitative loci (pQTL) genetic instruments on plasma and cerebrospinal fluid (CSF) were obtained from Fenland (discovery, n=10,709), deCODE (replication, n=35,559), and a recently published dataset (replication, n=971). To investigate the causal ALS-associated proteins, proteome-wide Mendelian randomization based on summary-data-based MR (SMR and multi-SNP-based SMR) were performed. Then, two-sample MR analyses using five additional methods were conducted as sensitivity analyses. To further address the linkage disequilibrium bias, heterogeneity in dependent instruments test and colocalization analyses were performed. Steiger filtering and bi-directional MR analyses were conducted to address the potential reverse causality. Four drug target datasets were searched to extract druggability profiles for candidate target proteins. In addition, we carried out a case-control study involving up to 21 patients with ALS and 21 matched controls to assess the protein levels difference in CSF for evidence triangulation.ResultsGenetically predicted levels of six circulating proteins were associated with incident ALS in primary SMR analysis. After removing proteins with any linkage disequilibrium bias, SHBG,SIGLEC7, and SIGLEC9presented consistent associations with ALS risk, supported by medium-to-high colocalization across both plasma pQTL datasets. In CSF, higher level ofSHBGwas also causally associated with the risk of ALS. There was no reverse causality detected. The case-control study using CSF proteomics conducted in our center observed consistent alteration in the levels ofSHBGandSIGLEC7with MR prediction, further suggesting their functionally relevant to ALS as potential druggable targets.DiscussionCombined with the findings from MR and our observational study, we prioritizeSHBG,SIGLEC7,andSIGLEC9as drug candidate proteins for ALS, and further studies are needed to verify our findings and elucidate the underlying mechanism.

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“…The BioFINDER study 85 is run by the Clinical Memory Research Unit and The Biomedical center, at Lund University, Sweden. Participants were recruited from the Memory and Neurology clinics at Skåne University Hospital as well as the Memory Clinic at Ängelholm’s Hospital.…”

Section: Methodsmentioning

confidence: 99%

Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-related disease risk and novel therapeutic targets

Zhao

Stacey

Eriksson

et al. 2023

Preprint

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Circulating proteins play key roles in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 15,150 participants. We identified 180 pQTLs, of which 50 were novel. Integration of pQTL data with eQTL and disease GWAS provided insights into pathogenesis, implicating lymphotoxin-alpha (LTA) in multiple sclerosis. Using Mendelian randomisation (MR), we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant causal roles for CD40 in rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Our results highlight novel potential therapeutic avenues, including CXCL5 in ulcerative colitis (UC), a finding supported by elevated gutCXCL5expression in UC patients. Our data provide a powerful resource to facilitate future drug target prioritization.

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The genetic regulation of protein expression in cerebrospinal fluid

Cited by 27 publications

References 63 publications

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Prioritization of therapeutic targets for amyotrophic lateral sclerosis using protein-wide Mendelian randomization analysis

Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-related disease risk and novel therapeutic targets

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