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

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

doi:10.1038/nn.4587

Cited by 337 publications

(351 citation statements)

References 83 publications

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“…GRN can adopt multiple subcellular localizations from lysosomes (as granulin) to the extracellular space (as progranulin) and exerts a negative control upon microglial activation in mouse models (see Fig 5; Martens et al, 2012). Interestingly, all of the prioritized AD risk genes are Spi1 targets, substantiating the pivotal role of this transcription factor in the observed Ab-induced transcriptional response (Gjoneska et al, 2015;Huang et al, 2017). The single microglia sequencing data demonstrate that 8 of the 18 prioritized genes are more highly expressed in homeostatic microglia (HM) than in activated microglia (ARM).…”

Section: Discussionmentioning

confidence: 67%

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

et al. 2020

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Polygenic risk scores have identified that genetic variants without genome‐wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy‐TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome‐wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

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Section: Discussionmentioning

confidence: 67%

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

et al. 2020

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“…5). Of interest, rs2071305 (but not rs11039131) was in LD with rs1057233 ( r 2 = 0.65, D ′ = 0.99), a SNP that has been associated with AD age of onset in a survival analysis [20]. Collectively, these results suggest several different AD-associated genetic variants within chromosome 11.…”

Section: Resultsmentioning

confidence: 96%

“…We identified rs2071305 and rs11039131 that were tagging variants within MYBPC3 and DDB2 , within the MTCH2 and SPI1 regions. Furthermore, rs2071305 was in LD with an AD age of onset SNP that was associated with lower expression of SPI1 in monocytes and macrophages [20, 22]. We found that SPI1 expression was altered in AD brains.…”

Section: Discussionmentioning

confidence: 93%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

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“…Similarly, PU.1 is a pioneer transcription factor with DNA methylation sensitive binding (Stephens and Poon, 2016) critical for microglia progenitor development (Kierdorf et al, 2013; Goldmann et al, 2016), regulates microglia specific enhancers (Gosselin et al, 2014) and gene expression (Satoh et al, 2014). PU.1 and shows increased expression in human ASD brain(Gupta et al, 2014), and manipulations of PU.1 alter the expression of key microglial genes and phagocytosis function (Huang et al, 2017), indicating that changes in PU.1 binding could dramatically alter microglial function in ASD. Future studies will be needed to examine the impact of MAA on microglia from different stages of development and in altering the transcriptional response to secondary immune activation (i.e.…”

Section: Discussionmentioning

confidence: 99%

Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism

Ciernia

Careaga

LaSalle

et al. 2017

Glia

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Dysregulation in immune responses during pregnancy increases the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive, and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.

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

Cited by 337 publications

References 83 publications

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism

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