Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

Fahri Küçükali; Alexander Neumann; Jasper Van Dongen; Tim De Pooter; Geert Joris; Peter De Rijk; Olena Ohlei; Valerija Dobricic; Isabelle Bos; Stephanie J B Vos; Sebastiaan Engelborghs; Ellen De Roeck; Rik Vandenberghe; Silvy Gabel; Karen Meersmans; Magda Tsolaki; Frans Verhey; Pablo Martinez-Lage; Mikel Tainta; Giovanni Frisoni; Oliver Blin; Jill C Richardson; Régis Bordet; Philip Scheltens; Julius Popp; Gwendoline Peyratout; Peter Johannsen; Lutz Frölich; Yvonne Freund-Levi; Johannes Streffer; Simon Lovestone; Cristina Legido-Quigley; Mara Ten Kate; Frederik Barkhof; Henrik Zetterberg; Lars Bertram; Mojca Strazisar; Pieter Jelle Visser; Christine Van Broeckhoven; Kristel Sleegers; Alzheimer's Disease Neuroimaging Initiative

doi:10.1002/alz.12842

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

Fahri Küçükali, Alexander Neumann, Jasper Van Dongen, Tim De Pooter, Geert Joris, Peter De Rijk, Olena Ohlei, Valerija Dobricic, Isabelle Bos, Stephanie J B Vos, Sebastiaan Engelborghs, Ellen De Roeck, Rik Vandenberghe, Silvy Gabel, Karen Meersmans, Magda Tsolaki, Frans Verhey, Pablo Martinez-Lage, Mikel Tainta, Giovanni FrisoniOliver Blin, Jill C Richardson, Régis Bordet, Philip Scheltens, Julius Popp, Gwendoline Peyratout, Peter Johannsen, Lutz Frölich, Yvonne Freund-Levi, Johannes Streffer, Simon Lovestone, Cristina Legido-Quigley, Mara Ten Kate, Frederik Barkhof, Henrik Zetterberg, Lars Bertram, Mojca Strazisar, Pieter Jelle Visser, Christine Van Broeckhoven, Kristel Sleegers^*, Alzheimer's Disease Neuroimaging Initiative

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.

METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).

RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.

DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

Original language	English
Pages (from-to)	2317-2331
Number of pages	15
Journal	Alzheimer's & Dementia
Volume	19
Issue number	6
Early online date	4 Dec 2022
DOIs	https://doi.org/10.1002/alz.12842
Publication status	Published - Jun 2023

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Cite this

Küçükali, F., Neumann, A., Van Dongen, J., De Pooter, T., Joris, G., De Rijk, P., Ohlei, O., Dobricic, V., Bos, I., Vos, S. J. B., Engelborghs, S., De Roeck, E., Vandenberghe, R., Gabel, S., Meersmans, K., Tsolaki, M., Verhey, F., Martinez-Lage, P., Tainta, M., ... Alzheimer's Disease Neuroimaging Initiative (2023). Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimer's & Dementia, 19(6), 2317-2331. https://doi.org/10.1002/alz.12842

@article{f614bf23fc124befbda3e2f04f1a3322,

title = "Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits",

abstract = "INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.",

author = "Fahri K{\"u}{\c c}{\"u}kali and Alexander Neumann and {Van Dongen}, Jasper and {De Pooter}, Tim and Geert Joris and {De Rijk}, Peter and Olena Ohlei and Valerija Dobricic and Isabelle Bos and Vos, {Stephanie J B} and Sebastiaan Engelborghs and {De Roeck}, Ellen and Rik Vandenberghe and Silvy Gabel and Karen Meersmans and Magda Tsolaki and Frans Verhey and Pablo Martinez-Lage and Mikel Tainta and Giovanni Frisoni and Oliver Blin and Richardson, {Jill C} and R{\'e}gis Bordet and Philip Scheltens and Julius Popp and Gwendoline Peyratout and Peter Johannsen and Lutz Fr{\"o}lich and Yvonne Freund-Levi and Johannes Streffer and Simon Lovestone and Cristina Legido-Quigley and Kate, {Mara Ten} and Frederik Barkhof and Henrik Zetterberg and Lars Bertram and Mojca Strazisar and Visser, {Pieter Jelle} and {Van Broeckhoven}, Christine and Kristel Sleegers and {Alzheimer's Disease Neuroimaging Initiative}",

note = "{\textcopyright} 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2023",

month = jun,

doi = "10.1002/alz.12842",

language = "English",

volume = "19",

pages = "2317--2331",

journal = "Alzheimer's & Dementia",

issn = "1552-5260",

publisher = "Elsevier Science",

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Küçükali, F, Neumann, A, Van Dongen, J, De Pooter, T, Joris, G, De Rijk, P, Ohlei, O, Dobricic, V, Bos, I, Vos, SJB, Engelborghs, S, De Roeck, E, Vandenberghe, R, Gabel, S, Meersmans, K, Tsolaki, M, Verhey, F, Martinez-Lage, P, Tainta, M, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Scheltens, P, Popp, J, Peyratout, G, Johannsen, P, Frölich, L, Freund-Levi, Y, Streffer, J, Lovestone, S, Legido-Quigley, C, Kate, MT, Barkhof, F, Zetterberg, H, Bertram, L, Strazisar, M, Visser, PJ, Van Broeckhoven, C, Sleegers, K & Alzheimer's Disease Neuroimaging Initiative 2023, 'Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits', Alzheimer's & Dementia, vol. 19, no. 6, pp. 2317-2331. https://doi.org/10.1002/alz.12842

TY - JOUR

T1 - Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

AU - Küçükali, Fahri

AU - Neumann, Alexander

AU - Van Dongen, Jasper

AU - De Pooter, Tim

AU - Joris, Geert

AU - De Rijk, Peter

AU - Ohlei, Olena

AU - Dobricic, Valerija

AU - Bos, Isabelle

AU - Vos, Stephanie J B

AU - Engelborghs, Sebastiaan

AU - De Roeck, Ellen

AU - Vandenberghe, Rik

AU - Gabel, Silvy

AU - Meersmans, Karen

AU - Tsolaki, Magda

AU - Verhey, Frans

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Frisoni, Giovanni

AU - Blin, Oliver

AU - Richardson, Jill C

AU - Bordet, Régis

AU - Scheltens, Philip

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Johannsen, Peter

AU - Frölich, Lutz

AU - Freund-Levi, Yvonne

AU - Streffer, Johannes

AU - Lovestone, Simon

AU - Legido-Quigley, Cristina

AU - Kate, Mara Ten

AU - Barkhof, Frederik

AU - Zetterberg, Henrik

AU - Bertram, Lars

AU - Strazisar, Mojca

AU - Visser, Pieter Jelle

AU - Van Broeckhoven, Christine

AU - Sleegers, Kristel

AU - Alzheimer's Disease Neuroimaging Initiative

PY - 2023/6

Y1 - 2023/6

N2 - INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

AB - INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

U2 - 10.1002/alz.12842

DO - 10.1002/alz.12842

M3 - Article

C2 - 36464806

SN - 1552-5260

VL - 19

SP - 2317

EP - 2331

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 6

ER -