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A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

by Kapoor, Manav , Lambert, Jean Charles , Schellenberg, Gerard D , Del-Aguila, Jorge L , Launer, Lenore , DeStefano, Anita , Borecki, Ingrid , Pimenova, Anna A , Sims, Rebecca , Hao, Ke , Cruchaga, Carlos , Marcora, Edoardo , Fairfax, Benjamin P , Mayeux, Richard , Czajkowski, Jake , van der Lee, Sven , Amouyel, Philippe , Fitzpatrick, Annette , Di Narzo, Antonio F , Harari, Oscar , Ibañez, Laura , Smith, Albert , Pericak-Vance, Margaret A , McKenzie, Andrew , Fernandez, Maria Victoria , Kauwe, John S K , Huang, Kuan-lin , Farrer, Lindsay A , Grenier-Boley, Benjamin , Ikram, M Arfan , Jin, Sheng Chih , Bellenguez, Céline , Bertelsen, Sarah , Seshadri, Sudha , Goate, Alison M , Raj, Towfique , Bis, Joshua C , van Duijn, Cornelia , Escott-Price, Valentina , Chouraki, Vincent , Budde, John , Williams, Julie , Zhang, Bin , Adams, Hieab H H , Haines, Jonathan L , Renton, Alan E , Deming, Yuetiva

in 38/39 / 38/43 / 38/77 / 45 / 631/114/2401 / 631/208/205/2138 / 692/699/375/365 / Alleles / Alzheimer Disease - genetics / Alzheimer's disease / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Techniques / Biomedicine / Development and progression / Disease control / Female / Gene expression / Genetic aspects / Genetic Predisposition to Disease / Genome-Wide Association Study - methods / Genomes / Haplotypes - genetics / Heritability / Humans / Linkage disequilibrium / Linkage Disequilibrium - genetics / Loci / Macrophages / Male / Mice / Microglia / Monocytes / Myeloid cells / Neurobiology / Neurodegenerative diseases / Neurosciences / Phagocytes / Physiological aspects / Polymorphism, Single Nucleotide - genetics / Proto-Oncogene Proteins - genetics / PU.1 protein / Regression analysis / Risk / Risk Factors / Rodents / Survival analysis / Trans-Activators - genetics / Transcription Factors - genetics

2017

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A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

2017

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A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

2017

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Journal Article

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

Kapoor, Manav,

Lambert, Jean Charles,

Schellenberg, Gerard D,

Del-Aguila, Jorge L,

Launer, Lenore,

DeStefano, Anita,

Borecki, Ingrid,

Pimenova, Anna A,

Sims, Rebecca,

Hao, Ke,

Cruchaga, Carlos,

Marcora, Edoardo,

Fairfax, Benjamin P,

Mayeux, Richard,

Czajkowski, Jake,

van der Lee, Sven,

Amouyel, Philippe,

Fitzpatrick, Annette,

Di Narzo, Antonio F,

Harari, Oscar,

Ibañez, Laura,

Smith, Albert,

Pericak-Vance, Margaret A,

McKenzie, Andrew,

Fernandez, Maria Victoria,

Kauwe, John S K,

Huang, Kuan-lin,

Farrer, Lindsay A,

Grenier-Boley, Benjamin,

Ikram, M Arfan,

Jin, Sheng Chih,

Bellenguez, Céline,

Bertelsen, Sarah,

Seshadri, Sudha,

Goate, Alison M,

Raj, Towfique,

Bis, Joshua C,

van Duijn, Cornelia,

Escott-Price, Valentina,

Chouraki, Vincent,

Budde, John,

Williams, Julie,

Zhang, Bin,

Adams, Hieab H H,

Haines, Jonathan L,

Renton, Alan E,

Deming, Yuetiva

2017

Overview

The authors identified a protective genetic allele associated with lower PU.1 ( SPI1 ) expression in myeloid cells by conducting a genome-wide scan of Alzheimer's disease (AD). PU.1 binds the promoters of AD-associated genes (e.g., CD33 , MS4A4A & MS4A6A , TYROBP ) and modulates their expression, suggesting it may reduce AD risk by regulating myeloid cell gene expression. A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

38/39

/ 38/43

/ 38/77

/ 45

/ 631/114/2401

/ 631/208/205/2138

/ 692/699/375/365