Immune-related genetic enrichment in frontotemporal dementia

An analysis of genome-wide association studies

International FTD-Genomics Consortium

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 (GWASs) (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 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show 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 FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Original languageEnglish (US)
Article numbere1002487
JournalPLoS medicine
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2018

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Frontotemporal Dementia
Genome-Wide Association Study
Immune System Diseases
HLA Antigens
Progressive Supranuclear Palsy
Rheumatoid Arthritis
Celiac Disease
Genetic Pleiotropy
Chromosomes, Human, Pair 6
Amyotrophic Lateral Sclerosis
Type 1 Diabetes Mellitus
Ulcerative Colitis
Single Nucleotide Polymorphism
DNA Transposable Elements
Linkage Disequilibrium
Microglia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{dc21bc1d0aec4110b92a097c2edc7963,
title = "Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies",
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 (GWASs) (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 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show 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 FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.",
author = "{International FTD-Genomics Consortium} and Iris Broce and Karch, {Celeste M.} and Natalie Wen and Fan, {Chun C.} and Yunpeng Wang and {Hong Tan}, Chin 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 Raffaele Ferrari and Hernandez, {Dena G.} and Nalls, {Michael A.} and Rohrer, {Jonathan D.} and Adaikalavan Ramasamy and Kwok, {John B.J.} and Carol Dobson-Stone and Brooks, {William S.} and Schofield, {Peter R.} and Halliday, {Glenda M.} and Hodges, {John R.} and Olivier Piguet and Lauren Bartley and Elizabeth Thompson and Eric Haan and Isabel Hern{\'a}ndez and Agust{\'i}n Ruiz and Merc{\`e} Boada and Barbara Borroni and Alessandro Padovani and Grafman, {Jordan Henry}",
year = "2018",
month = "1",
day = "1",
doi = "10.1371/journal.pmed.1002487",
language = "English (US)",
volume = "15",
journal = "PLoS Medicine",
issn = "1549-1277",
publisher = "Nature Publishing Group",
number = "1",

}

Immune-related genetic enrichment in frontotemporal dementia : An analysis of genome-wide association studies. / International FTD-Genomics Consortium.

In: PLoS medicine, Vol. 15, No. 1, e1002487, 01.01.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immune-related genetic enrichment in frontotemporal dementia

T2 - An analysis of genome-wide association studies

AU - International FTD-Genomics Consortium

AU - Broce, Iris

AU - Karch, Celeste M.

AU - Wen, Natalie

AU - Fan, Chun C.

AU - Wang, Yunpeng

AU - Hong Tan, Chin

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, Raffaele

AU - Hernandez, Dena G.

AU - Nalls, Michael A.

AU - Rohrer, Jonathan D.

AU - Ramasamy, Adaikalavan

AU - Kwok, John B.J.

AU - Dobson-Stone, Carol

AU - Brooks, William S.

AU - Schofield, Peter R.

AU - Halliday, Glenda M.

AU - Hodges, John R.

AU - Piguet, Olivier

AU - Bartley, Lauren

AU - Thompson, Elizabeth

AU - Haan, Eric

AU - Hernández, Isabel

AU - Ruiz, Agustín

AU - Boada, Mercè

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Grafman, Jordan Henry

PY - 2018/1/1

Y1 - 2018/1/1

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 (GWASs) (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 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show 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 FTD risk. 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 (GWASs) (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 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show 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 FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

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U2 - 10.1371/journal.pmed.1002487

DO - 10.1371/journal.pmed.1002487

M3 - Article

VL - 15

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 1

M1 - e1002487

ER -