Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Alexander Neumann; Olena Ohlei; Fahri Küçükali; Isabelle J Bos; Jigyasha Timsina; Stephanie Vos; Dmitry Prokopenko; Betty M Tijms; Ulf Andreasson; Kaj Blennow; Rik Vandenberghe; Philip Scheltens; Charlotte E Teunissen; Sebastiaan Engelborghs; Giovanni B Frisoni; Oliver Blin; Jill C Richardson; Régis Bordet; Alberto Lleó; Daniel Alcolea; Julius Popp; Thomas W Marsh; Priyanka Gorijala; Christopher Clark; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Richard J B Dobson; Cristina Legido-Quigley; Christine Van Broeckhoven; Rudolph E Tanzi; Mara Ten Kate; Christina M Lill; Frederik Barkhof; Carlos Cruchaga; Simon Lovestone; Johannes Streffer; Henrik Zetterberg; Pieter Jelle Visser; Kristel Sleegers; Lars Bertram; EMIF-AD & ADNI study group

doi:10.1186/s13073-023-01233-z

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Genome Med. 2023 Oct 4;15(1):79. doi: 10.1186/s13073-023-01233-z.

Authors

Alexander Neumann^#^{1

2

3}, Olena Ohlei^#⁴, Fahri Küçükali^{1

2}, Isabelle J Bos⁵, Jigyasha Timsina^{6

7}, Stephanie Vos⁸, Dmitry Prokopenko⁹, Betty M Tijms¹⁰, Ulf Andreasson^{11

12}, Kaj Blennow^{11

12}, Rik Vandenberghe^{13

14}, Philip Scheltens¹⁰, Charlotte E Teunissen¹⁵, Sebastiaan Engelborghs^{2

16}, Giovanni B Frisoni¹⁷, Oliver Blin¹⁸, Jill C Richardson¹⁹, Régis Bordet²⁰, Alberto Lleó^{21

22}, Daniel Alcolea^{21

22}, Julius Popp^{23

24}, Thomas W Marsh^{6

7

25}, Priyanka Gorijala^{6

7}, Christopher Clark²³, Gwendoline Peyratout²⁴, Pablo Martinez-Lage²⁶, Mikel Tainta^{26

27}, Richard J B Dobson^{28

29

30

31

32}, Cristina Legido-Quigley^{33

34}, Christine Van Broeckhoven^{2

35}, Rudolph E Tanzi⁹, Mara Ten Kate^{36

37}, Christina M Lill^{4

38

39}, Frederik Barkhof^{40

41}, Carlos Cruchaga^{6

7

42}, Simon Lovestone^{43

44}, Johannes Streffer^{2

45

46}, Henrik Zetterberg^{11

12

47

48

49}, Pieter Jelle Visser^{2

8

36}, Kristel Sleegers^{1

2}, Lars Bertram^{50

51}; EMIF-AD & ADNI 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 Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, Netherlands.
⁴ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, Lübeck, 23562, Germany.
⁵ Netherlands Institute for Health Services Research, Utrecht, Netherlands.
⁶ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁷ NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.
⁸ Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.
⁹ Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
¹¹ Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹³ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
¹⁴ Neurology Service, University Hospital Leuven, Leuven, Belgium.
¹⁵ Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
¹⁶ Department of Neurology and Memory Clinic, Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
¹⁷ Memory Center, Department of Rehabilitation and Geriatrics, Geneva University and University Hospitals, Geneva, Switzerland.
¹⁸ Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France.
¹⁹ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
²⁰ Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France.
²¹ Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
²² Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
²³ Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zurich, Switzerland.
²⁴ Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
²⁵ Division of Biology & Biomedical Sciences, Washington University in St. Louis, St Louis, MO, USA.
²⁶ Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
²⁷ Zumarraga Hospital, Osakidetza, Integrated Health Organization (OSI) Goierri-Urola Garia, Basque Country, Spain.
²⁸ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Boston, UK.
²⁹ NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
³⁰ Health Data Research UK London, University College London, London, UK.
³¹ Institute of Health Informatics, University College London, London, UK.
³² The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.
³³ Steno Diabetes Center, Copenhagen, Denmark.
³⁴ Institute of Pharmaceutical Science, King's College London, London, UK.
³⁵ Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
³⁶ Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands.
³⁷ Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
³⁸ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
³⁹ Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, UK.
⁴⁰ Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands.
⁴¹ Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK.
⁴² Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.
⁴³ Janssen Medical Ltd, Wycombe, UK.
⁴⁴ Department of Psychiatry, University of Oxford, Oxford, UK.
⁴⁵ AC Immune SA, Lausanne, Switzerland.
⁴⁶ Janssen R&D, LLC, Beerse, Belgium.
⁴⁷ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁴⁸ UK Dementia Research Institute, University College London, London, UK.
⁴⁹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
⁵⁰ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, Lübeck, 23562, Germany. [email protected].
⁵¹ Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway. [email protected].

^# Contributed equally.

Abstract

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.

Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.

Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.

Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Keywords: Alzheimer’s disease; Biomarkers; Cerebrospinal fluid (CSF); Dementia; Genome-wide association study (GWAS); Mediation; Multivariate analysis; Principal component analysis; Structural equation modeling.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Apolipoproteins E / genetics
Biomarkers
Female
Genome-Wide Association Study
Humans
Inflammation
Male
Membrane Proteins / genetics
Nerve Tissue Proteins / genetics
Receptors, N-Methyl-D-Aspartate / genetics
tau Proteins / genetics

Substances

tau Proteins
Biomarkers
Apolipoproteins E
TMEM106B protein, human
Membrane Proteins
Nerve Tissue Proteins
GRIN2D protein, human
Receptors, N-Methyl-D-Aspartate

Abstract

Publication types

MeSH terms

Substances

Grants and funding