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

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

doi:10.1038/nn.4587

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

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

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Abstract

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.

Original language	English
Pages (from-to)	1052-1061
Number of pages	10
Journal	Nature neuroscience
Volume	20
Issue number	8
DOIs	https://doi.org/10.1038/nn.4587
State	Published - Aug 1 2017

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Huang, K. L., Marcora, E., Pimenova, A. A., Di Narzo, A. F., Kapoor, M., Jin, S. C., Harari, O., Bertelsen, S., Fairfax, B. P., Czajkowski, J., Chouraki, V., Grenier-Boley, B., Bellenguez, C., Deming, Y., McKenzie, A., Raj, T., Renton, A. E., Budde, J., Smith, A., ... Goate, A. M. (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nature neuroscience, 20(8), 1052-1061. https://doi.org/10.1038/nn.4587

@article{6501b60326134442b7fa19b4be68ffcf,

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

abstract = "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.",

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

year = "2017",

month = aug,

day = "1",

doi = "10.1038/nn.4587",

language = "English",

volume = "20",

pages = "1052--1061",

journal = "Nature neuroscience",

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Huang, KL, Marcora, E, Pimenova, AA, Di Narzo, AF, Kapoor, M, Jin, SC, Harari, O, Bertelsen, S, Fairfax, BP, Czajkowski, J, Chouraki, V, Grenier-Boley, B, Bellenguez, C, Deming, Y, McKenzie, A, Raj, T, Renton, AE, Budde, J, Smith, A, Fitzpatrick, A, Bis, JC, DeStefano, A, Adams, HHH, Ikram, MA, Van Der Lee, S, Del-Aguila, JL, Fernandez, MV, Ibañez, L, Sims, R, Escott-Price, V, Mayeux, R, Haines, JL, Farrer, LA, Pericak-Vance, MA, Lambert, JC, Van Duijn, C, Launer, L, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Zhang, B, Borecki, I, Kauwe, JSK, Cruchaga, C, Hao, K & Goate, AM 2017, 'A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease', Nature neuroscience, vol. 20, no. 8, pp. 1052-1061. https://doi.org/10.1038/nn.4587

TY - JOUR

T1 - A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

AU - Huang, Kuan Lin

AU - Marcora, Edoardo

AU - Pimenova, Anna A.

AU - Di Narzo, Antonio F.

AU - Kapoor, Manav

AU - Jin, Sheng Chih

AU - Harari, Oscar

AU - Bertelsen, Sarah

AU - Fairfax, Benjamin P.

AU - Czajkowski, Jake

AU - Chouraki, Vincent

AU - Grenier-Boley, Benjamin

AU - Bellenguez, Céline

AU - Deming, Yuetiva

AU - McKenzie, Andrew

AU - Raj, Towfique

AU - Renton, Alan E.

AU - Budde, John

AU - Smith, Albert

AU - Fitzpatrick, Annette

AU - Bis, Joshua C.

AU - DeStefano, Anita

AU - Adams, Hieab H.H.

AU - Ikram, M. Arfan

AU - Van Der Lee, Sven

AU - Del-Aguila, Jorge L.

AU - Fernandez, Maria Victoria

AU - Ibañez, Laura

AU - Sims, Rebecca

AU - Escott-Price, Valentina

AU - Mayeux, Richard

AU - Haines, Jonathan L.

AU - Farrer, Lindsay A.

AU - Pericak-Vance, Margaret A.

AU - Lambert, Jean Charles

AU - Van Duijn, Cornelia

AU - Launer, Lenore

AU - Seshadri, Sudha

AU - Williams, Julie

AU - Amouyel, Philippe

AU - Schellenberg, Gerard D.

AU - Zhang, Bin

AU - Borecki, Ingrid

AU - Kauwe, John S.K.

AU - Cruchaga, Carlos

AU - Hao, Ke

AU - Goate, Alison M.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85019686113&partnerID=8YFLogxK

U2 - 10.1038/nn.4587

DO - 10.1038/nn.4587

M3 - Article

C2 - 28628103

AN - SCOPUS:85019686113

SN - 1097-6256

VL - 20

SP - 1052

EP - 1061

JO - Nature neuroscience

JF - Nature neuroscience

IS - 8

ER -

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

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