A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese

Jiang, Teng; Tan, Lan; Chen, Qi; Tan, Meng-Shan; Zhou, Junshan; Zhu, Xi-Chen; Lu, Huan; Wang, Hui-Fu; Zhang, Yingdong; Yu, Jin‐Tai

doi:10.1016/j.neurobiolaging.2016.02.023

Cited by 81 publications

(77 citation statements)

References 15 publications

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“…This is higher than the cohort-wide frequency of 0.043% and case frequency of 0.10% reported in a cohort of 2,342 Han Chinese individuals (Jiang et al, 2016) and likely due to our small sample size. In East Asian populations, the ExAC database frequency of rs150277350 is 0.069% (Lek et al, 2016).…”

Section: Discussioncontrasting

confidence: 74%

“…Unlike most of the TREM2 variants associated with AD risk in previous studies, the A192T variant does not produce an amino acid change in the extracellular domain of TREM2 (Jiang et al, 2016; Jin, 2014; Jin et al, 2014). Rather, the A192T variant is near the end of the transmembrane portion of TREM2, and thus may alter cell surface expression and AD risk by a distinct mechanism yet to be determined.…”

Section: Discussionmentioning

confidence: 64%

“…rs150277350 was found in one patient with AD and is predicted to be a missense mutation resulting in an alanine-to-threonine change at position 192 (A192T) in TREM2. Polyphen predicted the variant to be “benign” and SIFT predicted it to be “tolerated.” rs150277350 was previously reported as a potential modifier of AD risk in a recent report on a Chinese cohort screened for TREM2 variants (Jiang et al, 2016), but was not significant after multiple testing correction and was not functionally characterized. This patient’s clinical description is provided in detail in the Case Report section.…”

Section: Resultsmentioning

confidence: 97%

“…However, recent studies have identified rare variants other than R47H in TREM2 that were statistically associated with risk for AD (Jiang et al, 2016) in Han Chinese individuals. Our study aimed to replicate and discover new variants in TREM2 associated with AD in a cohort of elderly Chinese individuals living in the San Francisco Bay Area.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease

et al. 2017

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Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer’s disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD. We characterized this variant using biochemical cell surface expression assays and found that it significantly altered cell surface expression of the TREM2 protein. Together these data provide evidence that the A192T variant in TREM2 could contribute risk for AD. This study underscores the increasingly recognized role of immune-related processes in AD and highlights the importance of including diverse populations in research to identify genetic variation that contributes risk for AD and other neurodegenerative disorders.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease

et al. 2017

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“…Since mutations in the stalk region may affect the efficacy and precision of ADAM‐mediated shedding, we first determined the TREM2 cleavage site. Strikingly, ADAM‐mediated cleavage within the stalk region occurs C‐terminal to histidine 157 exactly where the AD‐associated variant p.H157Y is located (Guerreiro et al , ; Ma et al , ; Jiang et al , ; Song et al , ). Analysis of proteolytic processing of the mutant variant revealed that higher levels of sTREM2 are generated, a finding opposite to the reduced shedding observed for mutations within the Ig‐like domain such as p.T66M and p.Y38C (Kleinberger et al , ).…”

Section: Introductionmentioning

confidence: 99%

An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

et al. 2017

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Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)‐like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2‐dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C‐terminal to histidine 157, a position where an AD‐associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig‐like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full‐length TREM2 and lowers TREM2‐dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2.

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Genetics of A lzheimer's Disease

Brookes¹,

Morgan²

2017

Encyclopedia of Life Sciences

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Knowledge on the genetic aetiology of Alzheimer's disease has greatly increased over the past 20 years. We are now finding that more genetic variants than previously thought play a role in disease susceptibility. Key Concepts Advances in genetic research into a complex disorder. Alzheimer's disease (AD) is the most common form of dementia and is genetically heterogeneous. The APOE gene has the largest effect size on risk for AD, and is the most replicated finding. Understanding of the genetic risk factors for AD has been greatly increased by advancements in technology. Multiple gene have now been identified as being involved in the aetiology of AD, and have highlight biological pathways that may be affected. Still, these genes do not account for all of the estimated genetic aetiology and therefore variants with even smaller effect size are being investigated through polygenic risk score analysis.

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A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese

Cited by 81 publications

References 15 publications

Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease

Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease

An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

Genetics of A lzheimer's Disease

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