. 2023 Oct 4;15(1):79.

doi: 10.1186/s13073-023-01233-z.

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

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. lars.bertram@uni-luebeck.de.
⁵¹ Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway. lars.bertram@uni-luebeck.de.

^# Contributed equally.

PMID: 37794492
PMCID: PMC10548686
DOI: 10.1186/s13073-023-01233-z

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

Alexander Neumann et al. Genome Med. 2023.

. 2023 Oct 4;15(1):79.

doi: 10.1186/s13073-023-01233-z.

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 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. lars.bertram@uni-luebeck.de.
⁵¹ Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway. lars.bertram@uni-luebeck.de.

^# Contributed equally.

PMID: 37794492
PMCID: PMC10548686
DOI: 10.1186/s13073-023-01233-z

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.

PubMed Disclaimer

Conflict of interest statement

FB is on the steering committee or iDMC member for Biogen, Merck, Roche, EISAI, and Prothena. consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics, has research agreements with Merck, Biogen, GE Healthcare, Roche, and is co-founder and shareholder of Queen Square Analytics LTD; HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). AL is on the editorial board of Neurology and Brain Communications, has served at scientific advisory boards from Fujirebio-Europe, Nutricia, Roche-Genentech, Biogen, Grifols, and Roche Diagnostics, and has filed a patent application of synaptic markers in neurodegenerative diseases. D.A. participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). SL is currently an employee of Janssen Medical Ltd (UK), a co-founder of Akrivia Health Ltd (UK) and within the past 5 years has filed patents related to biomarkers unrelated to the current work and advised or given lectures for Merck, Optum Labs, and Eisai as well as having received grant funding from multiple companies as part of EU IMI programs and from Astra Zeneca. JP received consultation honoraria from Nestle Institute of Health Sciences, Ono Pharma, OM Pharma, and Fujirebio, unrelated to the submitted work. SE has served on scientific advisory boards for Biogen, Danone, icometrix, Novartis, Nutricia, and Roche and received unrestricted research grants from Janssen Pharmaceutica and ADx Neurosciences (paid to institution). JR was an employee at GSK and currently an employee at the MSD London Discovery Centre, U.K. CC has received research support from: GSK and EISAI. CC is a member of the advisory board of Vivid Genomics and Circular Genomics and owns stocks. The remaining authors declare that they have no competing interests.

Figures

**Fig. 1**
Path model of main findings. This path model summarizes the main-effect mediation model. Circles indicate principal components or latent variables, rectangles represent observed variables. Arrows either indicate PC loadings or structural regression paths. Thicker lines correspond to stronger loadings, solid structural paths are genome-wide significant (p < 5 × 10⁻⁸), and dashed lines are suggestive (p < 0.008). Coefficients indicate either the effect of one effect allele on a biomarker PC in SD, or the effect of one SD higher biomarker PC score on latent AD in SD. Note: all paths are adjusted for assessment age, sex, genetic ancestry, and study but are omitted from figure

**Fig. 2**
Manhattan plot (main-effect model). Results from GWAS of five CSF biomarker PC across both sexes. Each row represents a different PC as outcome. X-axis represents each chromosome and the y-axis the p-value of the SNP association with the outcome on a −log₁₀ scale. All analyses were adjusted for sex, genetic ancestry, and SNP array. Red line indicates genome-wide significance threshold (p = 5 × 10⁻⁸). Yellow line indicates suggestive threshold (p = 1 × 10⁻⁶). Vertical lines point towards genome-wide significant loci based on any model. P-values below 1 × 10⁻¹⁰ were winsorized to 1 × 10⁻¹⁰

**Fig. 3**
Manhattan plot (sex stratified). Results from GWAS of five CSF biomarker PC for males and females separately. Each row represents a different PC as outcome. Per outcome, results for males are depicted at the bottom and for females at the top. X-axis represents each chromosome and the y-axis the p-value of the SNP association with the outcome on a −log₁₀ scale. All analyses were adjusted for genetic ancestry and SNP array. Red line indicates genome-wide significance threshold (p = 5 × 10⁻⁸). Yellow line indicates suggestive threshold (p = 1 × 10⁻⁶). Vertical lines point towards genome-wide significant loci based on any model. P-values below 1 × 10⁻¹⁰ were winsorized to 1 × 10⁻¹⁰

**Fig. 4**
Regional plots for *TMEM106B*, *CHI3L1*, and *GRIN2D*. Each plot displays the p-values of SNP associations in either *TMEM106B*, *CHI3L1*, or *GRIN2D* loci. Statistics are derived from two studies. Orange dots represent p-values of association with biomarker PCs estimated in this study and back dots represent p-values of association with AD, as estimated in a separate GWAS on 1 million participants (Wightman et al. [42]). Regional plots were created with snpxplorer.net

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

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