17q21.31 Sub-Haplotypes Underlying H1-Associated Risk for Parkinson's Disease and Progressive Supranuclear Palsy Converge on Altered Glial Regulation

Bowles, Kathryn R.; Pugh, Derian A; Farrell, Kurt; Han, Natalia; Tcw, Julia; Liu, Y.; Liang, Shiang An; Lü, Qian; Bendl, Jaroslav; Fullard, John F.; Renton, Alan E.; Casella, Alicia; Iida, Megan A.; Bandrés‐Ciga, Sara; Gan‐Or, Ziv; Heutink, Peter; Siitonen, Ari; Bertelsen, Sarah; Karch, Celeste M.; Frucht, Steven J.; Kopell, Brian H.; Peter, Inga; Park, You Jeong; Crane, PK; Kauwe, John; Boehme, Kevin L.; Hoglinger, Guenter U.; Charney, Alexander; Roussos, Panagiotis; Jc, Wang; Poon, Wayne W.; Raj, Towfique; Crary, John F.; Goate, Alison

doi:10.2139/ssrn.3518538

Cited by 6 publications

(11 citation statements)

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“…The chromosome 17q21.31 locus is noteworthy for harboring the tau-encoding MAPT gene within a common 900 kb inversion-polymorphism ( 16 ), and is a major risk locus for PSP (H1 haplotype OR = 4-5) as well as AD, Parkinson’s disease (PD), and Corticobasal Degeneration (CBD) ( 12 ). 17q21.31 contains complex haplotypic sub-structural variation and extensive LD, hampering interrogation with traditional statistical genetics approaches.…”

Section: Resultsmentioning

confidence: 99%

“…Sporadic AD and PSP, both known as tauopathies because of the pathological deposition of tau in the brains of affected individuals (2), are complex polygenic traits with heritability estimates of between 40-80% (3,4). Over the last decade a number of genome-wide association studies (GWAS) have identified numerous susceptibility loci (5)(6)(7)(8)(9)(10)(11)(12). However, most of these loci fall in noncoding regions of the genome and encompass numerous variants due to linkage disequilibrium (LD), which has hampered the identification of underlying regulatory variants and associated risk genes (13)(14)(15).…”

Section: Main Textmentioning

confidence: 99%

“…However, most of these loci fall in noncoding regions of the genome and encompass numerous variants due to linkage disequilibrium (LD), which has hampered the identification of underlying regulatory variants and associated risk genes (13)(14)(15). This has posed a particular challenge for the interpretation of extended complex haplotypes harboring multiple independent association signals such as the H1 pan-neurodegenerative risk haplotype at 17q21.31 that includes the MAPT locus (12,16,17), and the AD risk locus at 19q13.32 that harbors APOE (18)(19)(20).…”

Section: Main Textmentioning

confidence: 99%

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Functional regulatory variants implicate distinct transcriptional networks in dementia

Cooper

Kosuri

et al. 2021

Preprint

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Predicting functionality of noncoding variation is one of the major challenges in modern genetics. We employed massively parallel reporter assays to screen 5,706 variants from genome-wide association studies for both Alzheimers disease (AD) and Progressive Supranuclear Palsy (PSP). We identified 320 functional regulatory polymorphisms (SigVars) comprising 27 of 34 unique tested loci, including multiple independent signals across the complex 17q21.31 region. We identify novel risk genes including PLEKHM1 in PSP and APOC1 in AD, and perform gene-editing to validate four distinct causal loci, confirming complement 4 (C4A) as a novel genetic risk factor for AD. Moreover, functional variants preferentially disrupt transcription factor binding sites that converge on enhancers with differential cell-type specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses support a novel mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk via their aggregate activity on specific transcriptional programs.

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Section: Resultsmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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Functional regulatory variants implicate distinct transcriptional networks in dementia

Cooper

Kosuri

et al. 2021

Preprint

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“…Early evidence suggests that in iPSC‐derived neurons and microglia from H1c haplotype families, chromatin is in an open state near single nucleotide polymorphisms that associate with PSP; however, this is not the case in iPSC‐derived astrocytes. Conversely, three other subhaplotypes (H1.1–H1.3) appear to associate with PD through expression of the astrocytic marker LRRC37A, with some variants being protective, and others increasing risk for PD 90 …”

Section: Phenotypic and Genetic Diversity Of Tauopathiesmentioning

confidence: 99%

“…Conversely, three other subhaplotypes (H1.1-H1.3) appear to associate with PD through expression of the astrocytic marker LRRC37A, with some variants being protective, and others increasing risk for PD. 90…”

Section: Phenotypic and Genetic Diversity Of Tauopathiesmentioning

confidence: 99%

Current directions in tau research: Highlights from Tau 2020

Sexton

Snyder

Beher

et al. 2021

Alzheimer's & Dementia

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Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and taurelated mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

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Cross-regional homeostatic and reactive glial signatures in multiple sclerosis

et al. 2022

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Multiple sclerosis (MS) is a multifocal and progressive inflammatory disease of the central nervous system (CNS). However, the compartmentalized pathology of the disease affecting various anatomical regions including gray and white matter and lack of appropriate disease models impede understanding of the disease. Utilizing single-nucleus RNA-sequencing and multiplex spatial RNA mapping, we generated an integrated transcriptomic map comprising leukocortical, cerebellar and spinal cord areas in normal and MS tissues that captures regional subtype diversity of various cell types with an emphasis on astrocytes and oligodendrocytes. While we found strong cross-regional diversity among glial subtypes in control tissue, regional signatures become more obscure in MS. This suggests that patterns of transcriptomic changes in MS are shared across regions and converge on specific pathways, especially those regulating cellular stress and immune activation. In addition, we found evidence that a subtype of white matter oligodendrocytes appearing across all three CNS regions adopt pro-remyelinating gene signatures in MS. In summary, our data suggest that cross-regional transcriptomic glial signatures overlap in MS, with different reactive glial cell types capable of either exacerbating or ameliorating pathology.

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17q21.31 Sub-Haplotypes Underlying H1-Associated Risk for Parkinson's Disease and Progressive Supranuclear Palsy Converge on Altered Glial Regulation

Cited by 6 publications

References 0 publications

Functional regulatory variants implicate distinct transcriptional networks in dementia

Functional regulatory variants implicate distinct transcriptional networks in dementia

Current directions in tau research: Highlights from Tau 2020

Cross-regional homeostatic and reactive glial signatures in multiple sclerosis

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