Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders

Yang, Chengran; Farias, Fabiana; Ibáñez, Laura; Suhy, Adam; Sadler, Brooke; Fernández, María Victoria; Wang, Fengxian; Bradley, Joseph; Eiffert, Brett; Bahena, Jorge Alberto; Budde, John; Li, Zeran; Dube, Umber; Sung, Yun Ju; Mihindukulasuriya, Kathie A.; Morris, John C.; Fagan, Anne M.; Perrin, Richard J.; Benitez, Bruno A.; Rhinn, Hervé; Harari, Oscar; Cruchaga, Carlos

doi:10.1038/s41593-021-00886-6

Cited by 165 publications

(232 citation statements)

References 71 publications

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“…For the Knight-ADRC data, levels of 1,305 proteins were quantified using the SOMAscan assay, a multiplexed, aptamer-based platform CSF (n = 717) [49]. Quality control was performed at the sample and aptamer levels using control aptamers (positive and negative controls) and calibrator samples.…”

Section: Methodsmentioning

confidence: 99%

“…Quality control was performed at the sample and aptamer levels using control aptamers (positive and negative controls) and calibrator samples. As described in detail [49], additional quality control was performed that included limit of detection cut-off, scale factor, coefficient of variation, and outlier variation. Only proteins with a call rate higher than 85% call rate were included.…”

Section: Association With Csf Proteomicsmentioning

confidence: 99%

“…A total of 713 proteins passed quality control. pQTL analyses was performed and reported in previous studies [49].…”

Section: Association With Csf Proteomicsmentioning

confidence: 99%

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Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Jansen

Lee

Gomez‐Fonseca

et al. 2022

Preprint

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Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8,074; replication n = 5,042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for amyloid beta 42 (Aβ42) and BIN1 for phosphorylated Tau (pTau). GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories (amyloid, astrocyte, processing & migration, and migration & motility) suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

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Section: Methodsmentioning

confidence: 99%

Section: Association With Csf Proteomicsmentioning

confidence: 99%

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Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Jansen

Lee

Gomez‐Fonseca

et al. 2022

Preprint

Self Cite

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“…The weights of protein were obtained from the most predictive model. The protein weights used in the current study were derived from [ 19 ] and the expression weights were derived from transcriptomic data generated from dPFC (CommonMind Consortium; n = 452) [ 20 , 21 ]. Later, we used FUSION to combine the genetic effect of stroke (stroke GWAS z-score) with the protein or expression weights by calculating the linear sum of z-score × weight for the independent SNPs at the locus to perform the PWAS or TWAS.…”

Section: Methodsmentioning

confidence: 99%

Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood

Chen

Huang

et al. 2022

J Transl Med

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Background Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes. Methods Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood. Results Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes. Conclusions Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies.

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“…93,94 More recently, similar methods have been applied to perform proteome-wide association studies by combining GWAS summary statistics with protein QTL, showing evidence for an association of E-selectin levels in plasma and cerebrospinal fluid or plasma MMP-12 levels with stroke risk. 95…”

Section: Multifactorial Strokementioning

confidence: 99%

Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives

Debette

Markus

2022

Circulation Research

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Stroke is the second leading cause of death worldwide and a complex, heterogeneous condition. In this review, we provide an overview of the current knowledge on monogenic and multifactorial forms of stroke, highlighting recent insight into the continuum between these. We describe how, in recent years, large-scale genome-wide association studies have enabled major progress in deciphering the genetic basis for stroke and its subtypes, although more research is needed to interpret these findings. We cover the potential of stroke genetics to reveal novel pathophysiological processes underlying stroke, to accelerate the discovery of new therapeutic approaches, and to identify individuals in the population who are at high risk of stroke and could be targeted for tailored preventative interventions.

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Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders

Cited by 165 publications

References 71 publications

Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood

Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives

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