Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility

Liu, Guiyou; Liu, Yongquan; Jiang, Qinghua; Jiang, Yixiang; Feng, Rennan; Zhang, Liangcai; Chen, Zugen; Li, Keshen; Liu, Jiafeng

doi:10.1007/s12035-015-9416-7

Cited by 51 publications

(42 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, CD33 is known to play a role in AD as shown by our group and others (1–3) and TREM2 has been implicated in frontotemporal dementia, PD and amyotrophic lateral sclerosis in addition to AD (4–9). In order to leverage GWAS findings for therapeutic targeting, the GWAS associations must first be translated to functional outcomes, as has been done for CD33 , where we demonstrated that the risk allele leads to increased CD33 expression on the surface of monocytes and to diminished internalization of amyloid-β 42 peptide, supporting a robust genotype-to-phenotype association for this AD single-nucleotide polymorphism (SNP) (1).…”

Section: Introductionmentioning

confidence: 63%

A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants

et al. 2017

View full text Add to dashboard Cite

Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro, especially in the large numbers of individuals needed for genetic studies. Here we demonstrate the effectiveness of an in vitro model system of human monocyte-derived microglia-like cells (MDMi) to recapitulate many aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer’s disease, Parkinson’s disease and multiple sclerosis in 94 healthy individuals. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the PILRB and LRRK2 loci, the cis-eQTL is found in the MDMi cells but not in peripheral monocytes, suggesting that differentiation leads to the acquisition of a cellular state, which uncovers the functional consequence of certain genetic variants. We further validated the effect of risk haplotypes at the protein level for PILRB and CD33, and we confirmed that the CD33 risk haplotype alters a functional outcome, phagocytosis, in MDMi. Finally, we hypothesize that the MDMi-specific increased LRRK2 gene expression could be the key functional outcome of the GWAS Parkinson’s disease LRKK2 SNP, rs76904798.

show abstract

Section: Introductionmentioning

confidence: 63%

A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants

et al. 2017

View full text Add to dashboard Cite

show abstract

“…TREM2 AD risk variants are rare, but carry roughly the same risk as a copy of the apolipoprotein E4 ( APOE4 ) allele and clearly link the innate immune system to neurodegenerative disease [19]. Beyond AD, TREM2 variants have been linked to other neurodegenerative diseases, including Parkinson’s disease [20, 21] and sporadic amyotrophic lateral sclerosis (ALS) [22], and fronto-temporal dementia [23, 24], though these non-AD associations have not been as widely reproduced [16]. The association of distinct variants with different diseases is born out on the protein level.…”

Section: Trem2 In Diseasementioning

confidence: 99%

TREM2-Ligand Interactions in Health and Disease

Kober

Brett

2017

Journal of Molecular Biology

180

166

View full text Add to dashboard Cite

The protein Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer’s disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases, recent advances in our understanding of TREM2, and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease-risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.

show abstract

“…Evidence shows that eQTL may modify gene expression and influence risk for human diseases [27–29]. In order to validate the effect of rs9929218 variant on CDH1 mRNA expression level, we performed eQTLs analysis using a large-scale dataset from the peripheral blood samples and multiple human tissues from GTEx.…”

Section: Discussionmentioning

confidence: 99%

CDH1 rs9929218 variant at 16q22.1 contributes to colorectal cancer susceptibility

Han

Liu

Lü³

et al. 2016

Oncotarget

Self Cite

View full text Add to dashboard Cite

Colorectal cancer (CRC) is the third most common cancer. Large-scale genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants in European ancestry including the CDH1 rs9929218. Following GWAS and candidate studies evaluated the association between the CDH1 rs9929218 polymorphism and CRC in European, Asian and American populations. However, these studies reported inconsistent associations. Evidence shows that rs9929218 may regulate different gene expressions in different human tissues. Here, we reevaluated this association using large-scale samples from 16 studies (n=131768) using a meta-analysis method. In heterogeneity test, we did not identify significant heterogeneity among these studies. Meta-analysis using fixed effect model showed significant association between rs9929218 and CRC (P=6.16E-21, odds ratio (OR) =0.92, 95% confidence interval (CI) 0.91-0.94). In order to validate the effect of rs9929218 variant on CDH1 expression, we further performed a functional analysis using two large-scale expression datasets. We identified significant regulation relation between rs9929218 variant and the expression of CDH1, ZFP90, RP11-354M1.2 and MCOLN2 by both cis-effect and trans-effect. In summary, our analysis highlights significant association between rs9929218 polymorphism and CRC susceptibility.

show abstract

Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility

Cited by 51 publications

References 30 publications

A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants

A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants

TREM2-Ligand Interactions in Health and Disease

CDH1 rs9929218 variant at 16q22.1 contributes to colorectal cancer susceptibility

Contact Info

Product

Resources

About