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

Fahri Küçükali^{1

2}, Alexander Neumann^{1

2}, Jasper Van Dongen^{1

2}, Tim De Pooter^{2

3}, Geert Joris^{2

3}, Peter De Rijk^{2

3}, Olena Ohlei⁴, Valerija Dobricic⁴, Isabelle Bos⁵, Stephanie J B Vos⁶, Sebastiaan Engelborghs^{2

7}, Ellen De Roeck^{2

8}, Rik Vandenberghe^{9

10}, Silvy Gabel^{9

10}, Karen Meersmans^{9

10}, Magda Tsolaki¹¹, Frans Verhey^{6

12

13}, Pablo Martinez-Lage¹⁴, Mikel Tainta¹⁴, Giovanni Frisoni^{15

16}, Oliver Blin¹⁷, Jill C Richardson¹⁸, Régis Bordet¹⁹; Alzheimer's Disease Neuroimaging Initiative (ADNI); Philip Scheltens²⁰, Julius Popp^{21

22}, Gwendoline Peyratout²³, Peter Johannsen²⁴, Lutz Frölich²⁵, Yvonne Freund-Levi^{26

27

28}, Johannes Streffer², Simon Lovestone^{29

30}, Cristina Legido-Quigley^{31

32}, Mara Ten Kate^{20

33}, Frederik Barkhof^{33

34}, Henrik Zetterberg^{35

36

37

38

39}, Lars Bertram^{4

40}, Mojca Strazisar^{2

3}, Pieter Jelle Visser^{6

20}, Christine Van Broeckhoven^{2

41}, Kristel Sleegers^{1

2}; EMIF-AD Study Group

Affiliations

¹ Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
² Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
³ Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁴ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
⁵ Netherlands Institute for Health Services Research, Utrecht, Netherlands.
⁶ Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.
⁷ Department of Neurology and Brussels Integrated Center for Brain and Memory (Bru-BRAIN), Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
⁸ Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
⁹ University Hospital Leuven, Leuven, Belgium.
¹⁰ Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
¹¹ 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece.
¹² Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, Netherlands.
¹³ School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
¹⁴ Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
¹⁵ Department of Psychiatry, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
¹⁶ RCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁷ Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France.
¹⁸ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevanage, United Kingdom.
¹⁹ Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France.
²⁰ Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands.
²¹ Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland.
²² Department of Psychiatry, Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
²³ Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
²⁴ Clinical Drug Development, Novo Nordisk, Copenhagen, Denmark.
²⁵ Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²⁶ School of Medical Sciences, Örebro University, Örebro, Sweden.
²⁷ Departments of Geriatrics, University Hospital Örebro, Örebro, Sweden.
²⁸ Department of Clinical Science and Education, Södertälje Hospital, Södersjukhuset Karolinska Institutet, Stockholm, Sweden.
²⁹ Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
³⁰ Janssen Medical Ltd, High Wycombe, United Kingdom.
³¹ Steno Diabetes Center, Copenhagen, Denmark.
³² Institute of Pharmaceutical Sciences, King's College London, London, United Kingdom.
³³ Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
³⁴ Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, United Kingdom.
³⁵ Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
³⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
³⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³⁸ UK Dementia Research Institute, University College London, London, United Kingdom.
³⁹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
⁴⁰ Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway.
⁴¹ Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.

PMID: 36464806
DOI: 10.1002/alz.12842

Free article

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

Fahri Küçükali et al. Alzheimers Dement. 2023 Jun.

Free article

. 2023 Jun;19(6):2317-2331.

doi: 10.1002/alz.12842. Epub 2022 Dec 4.

Authors

Affiliations

¹ Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
² Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
³ Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁴ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
⁵ Netherlands Institute for Health Services Research, Utrecht, Netherlands.
⁶ Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.
⁷ Department of Neurology and Brussels Integrated Center for Brain and Memory (Bru-BRAIN), Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
⁸ Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
⁹ University Hospital Leuven, Leuven, Belgium.
¹⁰ Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
¹¹ 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece.
¹² Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, Netherlands.
¹³ School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
¹⁴ Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
¹⁵ Department of Psychiatry, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
¹⁶ RCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁷ Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France.
¹⁸ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevanage, United Kingdom.
¹⁹ Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France.
²⁰ Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands.
²¹ Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland.
²² Department of Psychiatry, Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
²³ Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
²⁴ Clinical Drug Development, Novo Nordisk, Copenhagen, Denmark.
²⁵ Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²⁶ School of Medical Sciences, Örebro University, Örebro, Sweden.
²⁷ Departments of Geriatrics, University Hospital Örebro, Örebro, Sweden.
²⁸ Department of Clinical Science and Education, Södertälje Hospital, Södersjukhuset Karolinska Institutet, Stockholm, Sweden.
²⁹ Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
³⁰ Janssen Medical Ltd, High Wycombe, United Kingdom.
³¹ Steno Diabetes Center, Copenhagen, Denmark.
³² Institute of Pharmaceutical Sciences, King's College London, London, United Kingdom.
³³ Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
³⁴ Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, United Kingdom.
³⁵ Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
³⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
³⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³⁸ UK Dementia Research Institute, University College London, London, United Kingdom.
³⁹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
⁴⁰ Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway.
⁴¹ Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.

PMID: 36464806
DOI: 10.1002/alz.12842

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.

Keywords: Alzheimer's disease; biomarkers; endophenotypes; rare coding variants; whole-exome sequencing.

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References

REFERENCES

1. Gaugler J, James B, Johnson T, Reimer J, Weuve J. Alzheimer's disease facts and figures. Alzheimers Dement. 2021;17(3):327-406. https://doi.org/10.1002/alz.12328
1. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Prim. 2021;7(1):1-21. https://doi.org/10.1038/s41572-021-00269-y
1. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-367. https://doi.org/10.1016/S1474-4422(13)70044-9
1. Zetterberg H, Bendlin BB. Biomarkers for Alzheimer's disease - preparing for a new era of disease-modifying therapies. Mol Psychiatry. 2021;26(1):296-308. https://doi.org/10.1038/s41380-020-0721-9
1. Folstein MF, Folstein SE, McHugh PR. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. https://doi.org/10.1016/0022-3956(75)90026-6

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

Affiliations

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

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical