Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

Yokoyama, Jennifer S.; Wang, Yunpeng; Schork, Andrew J.; Thompson, Wesley K.; Karch, Celeste M.; Cruchaga, Carlos; McEvoy, Linda K.; Witoelar, Aree; Chen, Chi‐Hua; Holland, Dominic; Brewer, James B.; Franke, André; Dillon, William P.; Wilson, David M.; Mukherjee, Pratik; Hess, Christopher P.; Miller, Zachary A.; Bonham, Luke W.; Shen, Jeffrey; Rabinovici, Gil D.; Rosen, Howard J.; Miller, Bruce L.; Hyman, Bradley T.; Schellenberg, Gerard D.; Karlsen, Tom H.; Andreassen, Ole A.; Dale, Anders M.; Desikan, Rahul S.

doi:10.1001/jamaneurol.2016.0150

Cited by 152 publications

(147 citation statements)

References 31 publications

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…The role of the immune system in AD pathogenicity has been previously shown22, 25 and previous pathway analysis of the AD GWAS we assessed here showed enrichment in immune‐related pathways 24. Findings are strongest for the innate immune response, for instance association with the TREM2 gene, which in brain cells are primarily expressed on microglia 45, 46.…”

Section: Discussionsupporting

confidence: 51%

“…There is extensive functional and clinical evidence that immune dysfunction plays a key role in the pathogenesis of the relapse‐remitting phase of MS 20, 21. For AD, Yokoyama et al22 showed that eight variants were associated with both AD and immune‐mediated diseases, and there is further evidence from pathway analysis1, 23, 24 and from animal models 25. For PD, the role of the immune system has been suggested through pathway analyses,26, 27 animal models,28 and variants in the Human Leukocyte Antigen (HLA) region reaching statistical significance in GWASs 3, 29.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Gagliano

Pouget

Hardy

et al. 2016

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectivesWe assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.MethodsWe obtained large‐scale genome‐wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene‐set lists were enriched for genetic heritability. We compared our results to those from two gene‐set enrichment methods (Ingenuity Pathway Analysis and enrichr).ResultsThere were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results.InterpretationFor AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

show abstract

Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Gagliano

Pouget

Hardy

et al. 2016

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…In MS, the involvement of the immune system is evident and remains the primary target of all available treatments to date (Fernandez et al, 2016). In AD, the involvement of the immune system was recently emphasized by GWAS studies, linking immune genes to familiar AD susceptibility (Jiang et al, 2016; Yokoyama et al, 2016). Moreover, recent work suggests the involvement of complement system and microglia in early stage of AD development, before any overt brain amyloid pathology (Hong et al, 2016), and the role of T cells in later stages (Baruch et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

Louveau

Mesquita

Kipnis

2016

Neuron

147

119

View full text Add to dashboard Cite

Summary Lymphatic vasculature drains interstitial fluids, which contain the tissue’s waste products and ensures immune surveillance of the tissues, allowing immune-cell recirculation. Until recently the central nervous system (CNS) was considered to be devoid of a conventional lymphatic vasculature. The recent discovery in the meninges of a lymphatic network that drains the CNS calls into question classic models for the drainage of macromolecules and immune cells from the CNS. In the context of neurological disorders, the presence of a lymphatic system draining the CNS potentially offers a new player and a new avenue for therapy. In this review, we will attempt to integrate the known primary functions of the tissue lymphatic vasculature that exists in peripheral organs with the proposed function of meningeal lymphatic vessels in neurological disorders, specifically multiple sclerosis and Alzheimer’s disease. We propose that these (and potentially other) neurological afflictions can be viewed as diseases with neuro-lympho-vascular component and should be therapeutically targeted as such.

show abstract

“…8,9,20,21 The conjunction FDR is defined as the posterior probability that an SNP is null for either phenotype or for both simultaneously, given that the P values for both traits are as small, or smaller, than the P values for each trait individually (eAppendix 1 in the Supplement). 8,9 We used an overall FDR threshold of P < .05 to indicate statistical significance. Manhattan plots were constructed based on the ranking of the conjunction FDR to illustrate the genomic location of the shared genetic risk loci.…”

Section: Methodsmentioning

confidence: 99%

“…8–11 Using previously validated methods, we investigated the genetic overlap between ALS, FTD, PSP, CBD, AD, and PD. We then used molecular and bioinformatics approaches to begin to define the role that these shared risk genes play in neurodegeneration.…”

mentioning

confidence: 99%

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

et al. 2018

Self Cite

View full text Add to dashboard Cite

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.OBJECTIVES To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. DESIGN, SETTING, AND PARTICIPANTSIn this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. MAIN OUTCOMES AND MEASURESThe primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. RESULTS Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002

show abstract

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

Cited by 152 publications

References 31 publications

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

Contact Info

Product

Resources

About