Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease.
Alzheimer’s disease
C-reactive protein
apolipoprotein B-100
apolipoprotein E
blood proteins
insulin-like growth factor binding protein 2
mendelian randomization analysis
polygenic trait
vitamin D-binding protein
Journal
Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863
Informations de publication
Date de publication:
2021
2021
Historique:
pubmed:
31
8
2021
medline:
17
12
2021
entrez:
30
8
2021
Statut:
ppublish
Résumé
Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. 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). 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. For APOE ɛ3, 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. 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.
Sections du résumé
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 ɛ3, 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.
Identifiants
pubmed: 34459398
pii: JAD210462
doi: 10.3233/JAD-210462
pmc: PMC8609677
doi:
Substances chimiques
ApoE protein, human
0
Apolipoproteins E
0
Blood Proteins
0
Somatomedins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1825-1839Subventions
Organisme : British Heart Foundation
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : CIHR
Pays : Canada
Organisme : Medical Research Council
ID : MC_PC_17214
Pays : United Kingdom
Organisme : Alzheimer's Society
ID : 171
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Chief Scientist Office
Pays : United Kingdom
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