Immune-related genetic enrichment in frontotemporal dementia

International FTD-Genomics Consortium (IFGC)

doi:10.1101/157875

Immune-related genetic enrichment in frontotemporal dementia

International FTD-Genomics Consortium (IFGC)

Physical Medicine and Rehabilitation

Research output: Contribution to journal › Article › peer-review

Abstract

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with 'FTD-related disorders' namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) - and one or more immune-mediated diseases including Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2), TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types. Conclusions We show considerable immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/157875
State	Published - Jun 30 2017

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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@article{620e2efd3b174f209848f8bb51a8ea1f,

title = "Immune-related genetic enrichment in frontotemporal dementia",

abstract = "Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with 'FTD-related disorders' namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) - and one or more immune-mediated diseases including Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2), TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types. Conclusions We show considerable immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.",

author = "{International FTD-Genomics Consortium (IFGC)} and Iris Broce and Karch, {Celeste M.} and Natalie Wen and Fan, {Chun C.} and Yunpeng Wang and Tan, {Chin Hong} and Naomi Kouri and Ross, {Owen A.} and H{\"o}glinger, {G{\"u}nter U.} and Ulrich Muller and John Hardy and Parastoo Momeni and Hess, {Christopher P.} and Dillon, {William P.} and Miller, {Zachary A.} and Bonham, {Luke W.} and Rabinovici, {Gil D.} and Rosen, {Howard J.} and Schellenberg, {Gerard D.} and Andre Franke and Karlsen, {Tom H.} and Veldink, {Jan H.} and Raffaele Ferrari and Yokoyama, {Jennifer S.} and Miller, {Bruce L.} and Andreassen, {Ole A.} and Dale, {Anders M.} and Desikan, {Rahul S.} and Sugrue, {Leo P.} and R. Ferrari and Hernandez, {D. G.} and Nalls, {M. A.} and Rohrer, {J. D.} and A. Ramasamy and Kwok, {J. B.J.} and C. Dobson-Stone and Schofield, {P. R.} and Halliday, {G. M.} and Hodges, {J. R.} and O. Piguet and L. Bartley and E. Thompson and E. Haan and I. Hern{\'a}ndez and A. Ruiz and M. Boada and B. Borroni and A. Padovani and C. Cruchaga and J. Grafman",

note = "Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2017",

month = jun,

day = "30",

doi = "10.1101/157875",

language = "English (US)",

journal = "Free Radical Biology and Medicine",

issn = "0891-5849",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Immune-related genetic enrichment in frontotemporal dementia

AU - International FTD-Genomics Consortium (IFGC)

AU - Broce, Iris

AU - Karch, Celeste M.

AU - Wen, Natalie

AU - Fan, Chun C.

AU - Wang, Yunpeng

AU - Tan, Chin Hong

AU - Kouri, Naomi

AU - Ross, Owen A.

AU - Höglinger, Günter U.

AU - Muller, Ulrich

AU - Hardy, John

AU - Momeni, Parastoo

AU - Hess, Christopher P.

AU - Dillon, William P.

AU - Miller, Zachary A.

AU - Bonham, Luke W.

AU - Rabinovici, Gil D.

AU - Rosen, Howard J.

AU - Schellenberg, Gerard D.

AU - Franke, Andre

AU - Karlsen, Tom H.

AU - Veldink, Jan H.

AU - Ferrari, Raffaele

AU - Yokoyama, Jennifer S.

AU - Miller, Bruce L.

AU - Andreassen, Ole A.

AU - Dale, Anders M.

AU - Desikan, Rahul S.

AU - Sugrue, Leo P.

AU - Ferrari, R.

AU - Hernandez, D. G.

AU - Nalls, M. A.

AU - Rohrer, J. D.

AU - Ramasamy, A.

AU - Kwok, J. B.J.

AU - Dobson-Stone, C.

AU - Schofield, P. R.

AU - Halliday, G. M.

AU - Hodges, J. R.

AU - Piguet, O.

AU - Bartley, L.

AU - Thompson, E.

AU - Haan, E.

AU - Hernández, I.

AU - Ruiz, A.

AU - Boada, M.

AU - Borroni, B.

AU - Padovani, A.

AU - Cruchaga, C.

AU - Grafman, J.

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2017/6/30

Y1 - 2017/6/30

N2 - Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with 'FTD-related disorders' namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) - and one or more immune-mediated diseases including Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2), TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types. Conclusions We show considerable immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

AB - Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with 'FTD-related disorders' namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) - and one or more immune-mediated diseases including Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2), TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types. Conclusions We show considerable immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

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DO - 10.1101/157875

M3 - Article

AN - SCOPUS:85095619556

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

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