A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

Abstract Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic reson...

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Autores principales: Jun Young Park, Dongsoo Lee, Jang Jae Lee, Jungsoo Gim, Tamil Iniyan Gunasekaran, Kyu Yeong Choi, Sarang Kang, Ah Ra Do, Jinyeon Jo, Juhong Park, Kyungtaek Park, Donghe Li, Sanghun Lee, Hoowon Kim, Immanuel Dhanasingh, Suparna Ghosh, Seula Keum, Jee Hye Choi, Gyun Jee Song, Lee Sael, Sangmyung Rhee, Simon Lovestone, Eunae Kim, Seung Hwan Moon, Byeong C. Kim, SangYun Kim, Andrew J. Saykin, Kwangsik Nho, Sung Haeng Lee, Lindsay A. Farrer, Gyungah R. Jun, Sungho Won, Kun Ho Lee, for the Alzheimer’s Disease Neuroimaging Initiative
Formato: article
Lenguaje:EN
Publicado: Nature Publishing Group 2021
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Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Acceso en línea:https://doaj.org/article/717fe653514c4f929231143c114b0aec
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spelling oai:doaj.org-article:717fe653514c4f929231143c114b0aec2021-11-21T12:07:43ZA missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages10.1038/s41398-021-01680-52158-3188https://doaj.org/article/717fe653514c4f929231143c114b0aec2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41398-021-01680-5https://doaj.org/toc/2158-3188Abstract Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.Jun Young ParkDongsoo LeeJang Jae LeeJungsoo GimTamil Iniyan GunasekaranKyu Yeong ChoiSarang KangAh Ra DoJinyeon JoJuhong ParkKyungtaek ParkDonghe LiSanghun LeeHoowon KimImmanuel DhanasinghSuparna GhoshSeula KeumJee Hye ChoiGyun Jee SongLee SaelSangmyung RheeSimon LovestoneEunae KimSeung Hwan MoonByeong C. KimSangYun KimAndrew J. SaykinKwangsik NhoSung Haeng LeeLindsay A. FarrerGyungah R. JunSungho WonKun Ho Leefor the Alzheimer’s Disease Neuroimaging InitiativeNature Publishing GrouparticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENTranslational Psychiatry, Vol 11, Iss 1, Pp 1-9 (2021)
institution DOAJ
collection DOAJ
language EN
topic Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
spellingShingle Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Jun Young Park
Dongsoo Lee
Jang Jae Lee
Jungsoo Gim
Tamil Iniyan Gunasekaran
Kyu Yeong Choi
Sarang Kang
Ah Ra Do
Jinyeon Jo
Juhong Park
Kyungtaek Park
Donghe Li
Sanghun Lee
Hoowon Kim
Immanuel Dhanasingh
Suparna Ghosh
Seula Keum
Jee Hye Choi
Gyun Jee Song
Lee Sael
Sangmyung Rhee
Simon Lovestone
Eunae Kim
Seung Hwan Moon
Byeong C. Kim
SangYun Kim
Andrew J. Saykin
Kwangsik Nho
Sung Haeng Lee
Lindsay A. Farrer
Gyungah R. Jun
Sungho Won
Kun Ho Lee
for the Alzheimer’s Disease Neuroimaging Initiative
A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
description Abstract Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
format article
author Jun Young Park
Dongsoo Lee
Jang Jae Lee
Jungsoo Gim
Tamil Iniyan Gunasekaran
Kyu Yeong Choi
Sarang Kang
Ah Ra Do
Jinyeon Jo
Juhong Park
Kyungtaek Park
Donghe Li
Sanghun Lee
Hoowon Kim
Immanuel Dhanasingh
Suparna Ghosh
Seula Keum
Jee Hye Choi
Gyun Jee Song
Lee Sael
Sangmyung Rhee
Simon Lovestone
Eunae Kim
Seung Hwan Moon
Byeong C. Kim
SangYun Kim
Andrew J. Saykin
Kwangsik Nho
Sung Haeng Lee
Lindsay A. Farrer
Gyungah R. Jun
Sungho Won
Kun Ho Lee
for the Alzheimer’s Disease Neuroimaging Initiative
author_facet Jun Young Park
Dongsoo Lee
Jang Jae Lee
Jungsoo Gim
Tamil Iniyan Gunasekaran
Kyu Yeong Choi
Sarang Kang
Ah Ra Do
Jinyeon Jo
Juhong Park
Kyungtaek Park
Donghe Li
Sanghun Lee
Hoowon Kim
Immanuel Dhanasingh
Suparna Ghosh
Seula Keum
Jee Hye Choi
Gyun Jee Song
Lee Sael
Sangmyung Rhee
Simon Lovestone
Eunae Kim
Seung Hwan Moon
Byeong C. Kim
SangYun Kim
Andrew J. Saykin
Kwangsik Nho
Sung Haeng Lee
Lindsay A. Farrer
Gyungah R. Jun
Sungho Won
Kun Ho Lee
for the Alzheimer’s Disease Neuroimaging Initiative
author_sort Jun Young Park
title A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
title_short A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
title_full A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
title_fullStr A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
title_full_unstemmed A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
title_sort missense variant in sharpin mediates alzheimer’s disease-specific brain damages
publisher Nature Publishing Group
publishDate 2021
url https://doaj.org/article/717fe653514c4f929231143c114b0aec
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