Genetic identification of brain cell types underlying schizophrenia

Nature Genetics, Год журнала: 2018, Номер 50(6), С. 825 - 833

Опубликована: Май 20, 2018

Язык: Английский

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A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis

Nature, Год журнала: 2021, Номер 597(7878), С. 709 - 714

Опубликована: Сен. 8, 2021

Язык: Английский

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Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases

Nature Genetics, Год журнала: 2023, Номер 55(1), С. 44 - 53

Опубликована: Янв. 1, 2023

Язык: Английский

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Common brain disorders are associated with heritable patterns of apparent aging of the brain

Nature Neuroscience, Год журнала: 2019, Номер 22(10), С. 1617 - 1623

Опубликована: Сен. 24, 2019

Язык: Английский

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Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis

Nature Medicine, Год журнала: 2018, Номер 24(12), С. 1837 - 1844

Опубликована: Окт. 31, 2018

Язык: Английский

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The Role of Astrocytes in CNS Inflammation

Trends in Immunology, Год журнала: 2020, Номер 41(9), С. 805 - 819

Опубликована: Авг. 13, 2020

Язык: Английский

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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Nature Genetics, Год журнала: 2021, Номер 53(12), С. 1636 - 1648

Опубликована: Дек. 1, 2021

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted cross-ancestry genome-wide association study (GWAS) including 29,612 patients ALS 122,656 controls, which identified 15 loci. When combined 8,953 individuals whole-genome sequencing (6,538 patients, 2,415 controls) large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated loci were shared multiple traits within the spectrum but distinct enrichment patterns across brain regions cell types. Of environmental lifestyle factors obtained from literature, Mendelian randomization indicated causal role high cholesterol levels. The combination all signals reveals perturbations vesicle-mediated transport autophagy provides evidence cell-autonomous initiation glutamatergic neurons.

Язык: Английский

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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Nature Immunology, Год журнала: 2023, Номер 24(9), С. 1540 - 1551

Опубликована: Авг. 10, 2023

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted genome-wide protein quantitative trait locus (pQTL) study 91 plasma measured using the Olink Target platform 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration pQTL data with eQTL disease association studies provided insight into pathogenesis, implicating lymphotoxin-α multiple sclerosis. Using Mendelian randomization (MR) to assess causality etiology, both shared distinct effects specific across immune-mediated diseases, including directionally discordant CD40 risk rheumatoid arthritis versus sclerosis inflammatory bowel disease. MR implicated CXCL5 etiology ulcerative colitis (UC) show elevated gut transcript expression patients UC. These results targets existing drugs provide powerful resource facilitate future drug target prioritization.

Язык: Английский

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Genetic drug target validation using Mendelian randomisation

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Июнь 26, 2020

Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, inference undermined if genetic variants used instrument a factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how 'no horizontal pleiotropy assumption' strengthened when proteins are interest. Proteins typically proximal effectors processes encoded in genome. Moreover, targets most medicines, so MR studies drug becoming fundamental development. To enable such studies, introduce mathematical framework that contrasts with located more distally chain from gene We illustrate key model decisions analytical maximising power evaluating robustness analyses.

Язык: Английский

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Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

Frontiers in Neuroscience, Год журнала: 2021, Номер 15

Опубликована: Сен. 24, 2021

Microglia are the resident macrophages of central nervous system (CNS) acting as first line defense in brain by phagocytosing harmful pathogens and cellular debris. emerge from early erythromyeloid progenitors yolk sac enter developing before establishment a fully mature blood–brain barrier. In physiological conditions, during development, microglia contribute to CNS homeostasis supporting cell proliferation neural precursors. post-natal life, such cells preserving integrity neuronal circuits sculpting synapses. After injury, change their morphology down-regulate those genes homeostatic functions. However, it is still unclear whether changes accompanied molecular functional modifications that might pathological process. While comprehensive transcriptome analyses at single-cell level have identified specific gene perturbations occurring “pathological” microglia, precise protective/detrimental role neurological disorders far being elucidated. this review, results so obtained regarding neurodegenerative will be discussed. There solid sound evidence suggesting regulating functions disease pathology represent strategy develop future therapies aimed counteracting degeneration multiple sclerosis, Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis.

Язык: Английский

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