A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

Binbin Wang; Suying Bao; Zhigang Zhang; Xueya Zhou; Jing Wang; Yanhui Fan; Yan Zhang; Yan Li; Luhua Chen; Yizhen Jia; Jiang Li; Miaoxin Li; Wenhua Zheng; Nan Mu; Liqiu Wang; Zhe Yu; Dana S.M. Wong; Yalun Zhang; Joseph Kwan; Henry Ka-Fung Mak; Amirthagowri Ambalavanan; Sirui Zhou; Wangwei Cai; Jin Zheng; Shishu Huang; Guy A. Rouleau; Wanling Yang; Ekaterina Rogaeva; Xu Ma; Peter St George-Hyslop; Leung Wing Chu; You Qiang Song

doi:10.1016/j.neurobiolaging.2018.03.006

A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

Binbin Wang
, Suying Bao
, Zhigang Zhang
, Xueya Zhou
, Jing Wang
, Yanhui Fan
, Yan Zhang
, Yan Li
, Luhua Chen
, Yizhen Jia
, Jiang Li
, Miaoxin Li
, Wenhua Zheng
, Nan Mu
, Liqiu Wang
, Zhe Yu
, Dana S.M. Wong
, Yalun Zhang
, Joseph Kwan
, Henry Ka-Fung Mak

Amirthagowri Ambalavanan, Sirui Zhou, Wangwei Cai, Jin Zheng, Shishu Huang, Guy A. Rouleau, Wanling Yang, Ekaterina Rogaeva, Xu Ma, Peter St George-Hyslop, Leung Wing Chu, You Qiang Song

Research output: Journal article publication › Journal article › Academic research › peer-review

23 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.

Original language	English
Pages (from-to)	160.e1-160.e7
Journal	Neurobiology of Aging
Volume	68
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.03.006
Publication status	Published - Aug 2018
Externally published	Yes

Keywords

ApoE ɛ4-negative
Late-onset Alzheimer's disease
MLKL
Whole exome sequencing

ASJC Scopus subject areas

General Neuroscience
Ageing
Developmental Biology
Clinical Neurology
Geriatrics and Gerontology

More information

10.1016/j.neurobiolaging.2018.03.006

Cite this

Wang, B., Bao, S., Zhang, Z., Zhou, X., Wang, J., Fan, Y., Zhang, Y., Li, Y., Chen, L., Jia, Y., Li, J., Li, M., Zheng, W., Mu, N., Wang, L., Yu, Z., Wong, D. S. M., Zhang, Y., Kwan, J., ... Song, Y. Q. (2018). A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population. Neurobiology of Aging, 68, 160.e1-160.e7. https://doi.org/10.1016/j.neurobiolaging.2018.03.006

@article{9dda0efd4f0b471fb3e1232bbfe0c4c4,

title = "A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population",

abstract = "Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.",

keywords = "ApoE ɛ4-negative, Late-onset Alzheimer's disease, MLKL, Whole exome sequencing",

author = "Binbin Wang and Suying Bao and Zhigang Zhang and Xueya Zhou and Jing Wang and Yanhui Fan and Yan Zhang and Yan Li and Luhua Chen and Yizhen Jia and Jiang Li and Miaoxin Li and Wenhua Zheng and Nan Mu and Liqiu Wang and Zhe Yu and Wong, \{Dana S.M.\} and Yalun Zhang and Joseph Kwan and \{Ka-Fung Mak\}, Henry and Amirthagowri Ambalavanan and Sirui Zhou and Wangwei Cai and Jin Zheng and Shishu Huang and Rouleau, \{Guy A.\} and Wanling Yang and Ekaterina Rogaeva and Xu Ma and \{St George-Hyslop\}, Peter and Chu, \{Leung Wing\} and Song, \{You Qiang\}",

note = "Funding Information: This work was supported by grants from the National Natural Science Foundation of China (YQS No. 81271226), Independent Innovation Program of National Research Institute of Family Planning of China, and the National Infrastructure of Chinese Genetic Resources (YCZYPT[2017]01-6). In part, this work was also supported by Wellcome Trust, Medical Research Council, Canadian Institute of Health Research, and National Institutes of Health. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = aug,

doi = "10.1016/j.neurobiolaging.2018.03.006",

language = "English",

volume = "68",

pages = "160.e1--160.e7",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

Wang, B, Bao, S, Zhang, Z, Zhou, X, Wang, J, Fan, Y, Zhang, Y, Li, Y, Chen, L, Jia, Y, Li, J, Li, M, Zheng, W, Mu, N, Wang, L, Yu, Z, Wong, DSM, Zhang, Y, Kwan, J, Ka-Fung Mak, H, Ambalavanan, A, Zhou, S, Cai, W, Zheng, J, Huang, S, Rouleau, GA, Yang, W, Rogaeva, E, Ma, X, St George-Hyslop, P, Chu, LW & Song, YQ 2018, 'A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population', Neurobiology of Aging, vol. 68, pp. 160.e1-160.e7. https://doi.org/10.1016/j.neurobiolaging.2018.03.006

TY - JOUR

T1 - A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

AU - Wang, Binbin

AU - Bao, Suying

AU - Zhang, Zhigang

AU - Zhou, Xueya

AU - Wang, Jing

AU - Fan, Yanhui

AU - Zhang, Yan

AU - Li, Yan

AU - Chen, Luhua

AU - Jia, Yizhen

AU - Li, Jiang

AU - Li, Miaoxin

AU - Zheng, Wenhua

AU - Mu, Nan

AU - Wang, Liqiu

AU - Yu, Zhe

AU - Wong, Dana S.M.

AU - Zhang, Yalun

AU - Kwan, Joseph

AU - Ka-Fung Mak, Henry

AU - Ambalavanan, Amirthagowri

AU - Zhou, Sirui

AU - Cai, Wangwei

AU - Zheng, Jin

AU - Huang, Shishu

AU - Rouleau, Guy A.

AU - Yang, Wanling

AU - Rogaeva, Ekaterina

AU - Ma, Xu

AU - St George-Hyslop, Peter

AU - Chu, Leung Wing

AU - Song, You Qiang

N1 - Funding Information: This work was supported by grants from the National Natural Science Foundation of China (YQS No. 81271226), Independent Innovation Program of National Research Institute of Family Planning of China, and the National Infrastructure of Chinese Genetic Resources (YCZYPT[2017]01-6). In part, this work was also supported by Wellcome Trust, Medical Research Council, Canadian Institute of Health Research, and National Institutes of Health. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/8

Y1 - 2018/8

N2 - Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.

AB - Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.

KW - ApoE ɛ4-negative

KW - Late-onset Alzheimer's disease

KW - MLKL

KW - Whole exome sequencing

UR - https://www.scopus.com/pages/publications/85045204367

U2 - 10.1016/j.neurobiolaging.2018.03.006

DO - 10.1016/j.neurobiolaging.2018.03.006

M3 - Journal article

C2 - 29656768

AN - SCOPUS:85045204367

SN - 0197-4580

VL - 68

SP - 160.e1-160.e7

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

Abstract

Keywords

ASJC Scopus subject areas

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