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

Fahri Küçükali; Alexander Neumann; the EMIF-AD Study Group; for the Alzheimer's Disease Neuroimaging Initiative; 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

doi:10.1002/alz.12842

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

Fahri Küçükali, Alexander Neumann, the EMIF-AD Study Group, for the Alzheimer's Disease Neuroimaging Initiative, 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-LageMikel 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^*

^*Corresponding author for this work

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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
Journal	Alzheimer's and Dementia
DOIs	https://doi.org/10.1002/alz.12842
Publication status	E-pub ahead of print - 4 Dec 2022

Bibliographical note

Funding Information:
EMIF: The present study was conducted as part of the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) project, which has received support from the Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) grant agreement no. 115372, the European Prevention of Alzheimer's Dementia (EPAD) grant no. 115736, and from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 666992, resources of which are composed of financial contributions from the European Union's Seventh Framework Program (FP7/2007‐2013) and the European Federation of Pharmaceutical Industries and Association (EFPIA) companies' in‐kind contribution. The Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study was funded by the European Commission within the fifth framework program (QLRT‐2001‐2455). The Beta Amyloid Oligomers in Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian Gipuzkoa Alzheimer Project (GAP) study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant nos. 11020, 13007, and 15005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation ‐ Alzheimer Research Switzerland (grant no. 2017‐PI01). F.K. is recipient of a PhD fellowship of the University of Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018‐02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG‐720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (no. 201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (nos. ADSF‐21‐831376‐C, ADSF‐21‐831381‐C, and ADSF‐21‐831377‐C), the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019‐0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. F.B. is supported by the National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH). This work was supported for Y.F‐L. by grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensförbundet, Brain Foundation “Hjärnfonden” (grant FO2018‐0315), “Särfond 31 Forskning Senil demens,” Region Örebro län, “Stiftelsen for Gamla Tjänarinnor,” and Demensfonden, Stockholm and Nyckelfonden Region Örebro Län.

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© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

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Alzheimer s Dementia - 2022 - K kali - Whole‐exome rare‐variant analysis of Alzheimer s disease and related biomarkerFinal published version, 1.23 MBLicence: CC BY-NC-ND

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Küçükali, F., Neumann, A., the EMIF-AD Study Group, for the Alzheimer's Disease Neuroimaging Initiative, 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., ... Sleegers, K. (2022). Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimer's and Dementia. https://doi.org/10.1002/alz.12842

@article{7c1151a8c59a4cc08f0caac3c0d416fc,

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 {the EMIF-AD Study Group} and {for the Alzheimer's Disease Neuroimaging Initiative} 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",

note = "Funding Information: EMIF: The present study was conducted as part of the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) project, which has received support from the Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) grant agreement no. 115372, the European Prevention of Alzheimer's Dementia (EPAD) grant no. 115736, and from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 666992, resources of which are composed of financial contributions from the European Union's Seventh Framework Program (FP7/2007‐2013) and the European Federation of Pharmaceutical Industries and Association (EFPIA) companies' in‐kind contribution. The Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study was funded by the European Commission within the fifth framework program (QLRT‐2001‐2455). The Beta Amyloid Oligomers in Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian Gipuzkoa Alzheimer Project (GAP) study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant nos. 11020, 13007, and 15005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation ‐ Alzheimer Research Switzerland (grant no. 2017‐PI01). F.K. is recipient of a PhD fellowship of the University of Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018‐02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG‐720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (no. 201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (nos. ADSF‐21‐831376‐C, ADSF‐21‐831381‐C, and ADSF‐21‐831377‐C), the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen f{\"o}r Gamla Tj{\"a}narinnor, Hj{\"a}rnfonden, Sweden (#FO2019‐0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska‐Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. F.B. is supported by the National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH). This work was supported for Y.F‐L. by grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensf{\"o}rbundet, Brain Foundation “Hj{\"a}rnfonden” (grant FO2018‐0315), “S{\"a}rfond 31 Forskning Senil demens,” Region {\"O}rebro l{\"a}n, “Stiftelsen for Gamla Tj{\"a}narinnor,” and Demensfonden, Stockholm and Nyckelfonden Region {\"O}rebro L{\"a}n. Publisher Copyright: {\textcopyright} 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2022",

month = dec,

day = "4",

doi = "10.1002/alz.12842",

language = "English",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

}

Küçükali, F, Neumann, A, the EMIF-AD Study Group, for the Alzheimer's Disease Neuroimaging Initiative, 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 2022, 'Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits', Alzheimer's and Dementia. 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 - the EMIF-AD Study Group

AU - for the Alzheimer's Disease Neuroimaging Initiative

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

N1 - Funding Information: EMIF: The present study was conducted as part of the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) project, which has received support from the Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) grant agreement no. 115372, the European Prevention of Alzheimer's Dementia (EPAD) grant no. 115736, and from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 666992, resources of which are composed of financial contributions from the European Union's Seventh Framework Program (FP7/2007‐2013) and the European Federation of Pharmaceutical Industries and Association (EFPIA) companies' in‐kind contribution. The Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study was funded by the European Commission within the fifth framework program (QLRT‐2001‐2455). The Beta Amyloid Oligomers in Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian Gipuzkoa Alzheimer Project (GAP) study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant nos. 11020, 13007, and 15005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation ‐ Alzheimer Research Switzerland (grant no. 2017‐PI01). F.K. is recipient of a PhD fellowship of the University of Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018‐02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG‐720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (no. 201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (nos. ADSF‐21‐831376‐C, ADSF‐21‐831381‐C, and ADSF‐21‐831377‐C), the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019‐0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. F.B. is supported by the National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH). This work was supported for Y.F‐L. by grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensförbundet, Brain Foundation “Hjärnfonden” (grant FO2018‐0315), “Särfond 31 Forskning Senil demens,” Region Örebro län, “Stiftelsen for Gamla Tjänarinnor,” and Demensfonden, Stockholm and Nyckelfonden Region Örebro Län. Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

PY - 2022/12/4

Y1 - 2022/12/4

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.

UR - http://www.scopus.com/inward/record.url?scp=85144049519&partnerID=8YFLogxK

U2 - 10.1002/alz.12842

DO - 10.1002/alz.12842

M3 - Article

C2 - 36464806

AN - SCOPUS:85144049519

SN - 1552-5260

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

ER -

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

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