Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease

Alzheimer’s Disease Neuroimaging Initiative

doi:10.3233/JAD-210462

Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease

Alzheimer’s Disease Neuroimaging Initiative

Univ London, Birkbeck University London, University College London, University of London Royal Veterinary College, University of London, St Georges University London, Imperial College London, Kings College London, Royal Holloway University London, Queen Mary University London, Div Populat Hlth Sci & Educ
King's College London
Psychology and Neuroscience
SLaM South London and Maudsley NHS Foundation Trust
Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway Department of NVS, Neurobiology Ward Sciences and Society, Alzheimer's Disease Research Center, Karolinska Institutet, Stockholm, Sweden.
Stravanger University Hospital
Department of Old Age Psychiatry
Institute of Health Informatics

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

6 Citations (Scopus)

Abstract

Background: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ϵ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

Original language	English
Pages (from-to)	1825-1839
Number of pages	15
Journal	JOURNAL OF ALZHEIMERS DISEASE
Volume	83
Issue number	4
Early online date	25 Aug 2021
DOIs	https://doi.org/10.3233/JAD-210462
Publication status	Published - 2021

Keywords

Alzheimer's disease
apolipoprotein B-100
apolipoprotein E
blood proteins
C-reactive protein
insulin-like growth factor binding protein 2
mendelian randomization analysis
polygenic trait
vitamin D-binding protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3233/JAD-210462

Cite this

@article{fdcf0930e58d42e19cb0a59341b8785c,

title = "Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease",

abstract = "Background: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ϵ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.",

keywords = "Alzheimer's disease, apolipoprotein B-100, apolipoprotein E, blood proteins, C-reactive protein, insulin-like growth factor binding protein 2, mendelian randomization analysis, polygenic trait, vitamin D-binding protein",

author = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative} and Alex Handy and Jodie Lord and Rebecca Green and Jin Xu and Dag Aarsland and Latha Velayudhan and Abdul Hye and Richard Dobson and Petroula Proitsi",

note = "Funding Information: This study represents independent research additionally funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: A proportion of data collection and sharing for this project was also funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. Funding Information: GERAD1 Acknowledgments: Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer{\textquoteright}s Research UK (ARUK) and the Welsh Assembly Government. Cambridge University and Kings College London acknowledge support from the MRC. ARUK supported sample collections at the South West Dementia Bank and the Universities of Nottingham, Manchester, and Belfast. The Belfast group acknowledges support from the Alzheimer{\textquoteright}s Society, Ulster Garden Villages, N. Ireland R&D Office, and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer{\textquoteright}s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer{\textquoteright}s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation, and the Charles and Joanne Knight Alzheimer{\textquoteright}s Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and NIHR Queen Square Dementia Biomedical Research Unit. LASER-AD was funded by Lundbeck SA. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The GERAD1 Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Funding Information: The authors acknowledge use of the research computing facility at King{\textquoteright}s College London, Ros- alind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy{\textquoteright}s & St. Thomas{\textquoteright} NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy{\textquoteright}s & St. Thomas{\textquoteright} Charity (TR130505). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King{\textquoteright}s College London, or the Department of Health and Social Care. Funding Information: This study provides evidence that apolipoproteins and CRP PRS are associated with AD and identifies a genetic signal linked to a specific, accessible risk factor. However, none of the proteins tested in MR demonstrated evidence of causality. This study was conducted in a moderate sample size and may have lacked the statistical power to identify true causal associations. Therefore, this study provides a This work was also made possible only through generous funding from key funding bodies. Petroula Proitsi is funded by Alzheimer{\textquoteright}s Research UK. Jodie Lord is funded by the van Geest endowment fund. Richard Dobson is supported by the following: (1) NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London, London, UK; (2) Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust; (3) The BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No. 116074. This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and EFPIA; it is chaired by DE Grobbee and SD Anker, partnering with 20 academic and industry partners and ESC; (4) the National Institute for Health Research University College London Hospitals Biomedical Research Centre; (5) the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London; (6) the UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare; (7) the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King{\textquoteright}s College Hospital NHS Foundation Trust. Publisher Copyright: {\textcopyright} 2021 - The authors. Published by IOS Press.",

year = "2021",

doi = "10.3233/JAD-210462",

language = "English",

volume = "83",

pages = "1825--1839",

journal = "JOURNAL OF ALZHEIMERS DISEASE",

issn = "1387-2877",

publisher = "IOS Press BV",

number = "4",

}

TY - JOUR

T1 - Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease

AU - Alzheimer’s Disease Neuroimaging Initiative

AU - Handy, Alex

AU - Lord, Jodie

AU - Green, Rebecca

AU - Xu, Jin

AU - Aarsland, Dag

AU - Velayudhan, Latha

AU - Hye, Abdul

AU - Dobson, Richard

AU - Proitsi, Petroula

N1 - Funding Information: This study represents independent research additionally funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: A proportion of data collection and sharing for this project was also funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. Funding Information: GERAD1 Acknowledgments: Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer’s Research UK (ARUK) and the Welsh Assembly Government. Cambridge University and Kings College London acknowledge support from the MRC. ARUK supported sample collections at the South West Dementia Bank and the Universities of Nottingham, Manchester, and Belfast. The Belfast group acknowledges support from the Alzheimer’s Society, Ulster Garden Villages, N. Ireland R&D Office, and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer’s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer’s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation, and the Charles and Joanne Knight Alzheimer’s Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and NIHR Queen Square Dementia Biomedical Research Unit. LASER-AD was funded by Lundbeck SA. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The GERAD1 Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Funding Information: The authors acknowledge use of the research computing facility at King’s College London, Ros- alind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy’s & St. Thomas’ NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy’s & St. Thomas’ Charity (TR130505). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. Funding Information: This study provides evidence that apolipoproteins and CRP PRS are associated with AD and identifies a genetic signal linked to a specific, accessible risk factor. However, none of the proteins tested in MR demonstrated evidence of causality. This study was conducted in a moderate sample size and may have lacked the statistical power to identify true causal associations. Therefore, this study provides a This work was also made possible only through generous funding from key funding bodies. Petroula Proitsi is funded by Alzheimer’s Research UK. Jodie Lord is funded by the van Geest endowment fund. Richard Dobson is supported by the following: (1) NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, London, UK; (2) Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust; (3) The BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No. 116074. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA; it is chaired by DE Grobbee and SD Anker, partnering with 20 academic and industry partners and ESC; (4) the National Institute for Health Research University College London Hospitals Biomedical Research Centre; (5) the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; (6) the UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare; (7) the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King’s College Hospital NHS Foundation Trust. Publisher Copyright: © 2021 - The authors. Published by IOS Press.

PY - 2021

Y1 - 2021

N2 - Background: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ϵ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

AB - Background: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ϵ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

KW - Alzheimer's disease

KW - apolipoprotein B-100

KW - apolipoprotein E

KW - blood proteins

KW - C-reactive protein

KW - insulin-like growth factor binding protein 2

KW - mendelian randomization analysis

KW - polygenic trait

KW - vitamin D-binding protein

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U2 - 10.3233/JAD-210462

DO - 10.3233/JAD-210462

M3 - Article

C2 - 34459398

SN - 1387-2877

VL - 83

SP - 1825

EP - 1839

JO - JOURNAL OF ALZHEIMERS DISEASE

JF - JOURNAL OF ALZHEIMERS DISEASE

IS - 4

ER -

Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease

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UN SDGs

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