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Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis.

Publication ,  Journal Article
Kulminski, AM; Loiko, E; Loika, Y; Culminskaya, I
Published in: GeroScience
February 2022

Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer's disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic associations with these phenotypes may shed light on EDU-related protection against AD. We performed pleiotropic meta-analyses using Fisher's method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5 × 10-8 < p < 0.1) and genome-wide (p ≤ 5 × 10-8) significance levels. We report 53 SNPs that attained p ≤ 5 × 10-8 at least in one of the pleiotropic meta-analyses and were reported in the univariate GWAS at 5 × 10-8 < p < 0.1. Of them, there were 46 pleiotropic SNPs according to Fisher's method. Additionally, Fisher's method identified 25 of 206 SNPs with pleiotropic effects, which attained p ≤ 5 × 10-8 in the univariate GWAS. We showed that a large fraction of the pleiotropic associations was affected by a counterintuitive phenomenon of antagonistic genetic heterogeneity, which explains the increase, rather than decrease, of the significance of the pleiotropic associations in the omnibus test. Functional enrichment analysis showed that apart from cancers, gene set harboring the non-pleiotropic SNPs was characterized by late-onset AD and neurodevelopmental disorders. The pleiotropic gene set was characterized by a broad spectrum of progressive neurological and neuromuscular diseases and immune-mediated conditions, including progressive motor neuropathy, multiple sclerosis, Parkinson's disease, and severe AD. Our results suggest that disentangling genes harboring variants with and without pleiotropic associations with AD and EDU is promising for dissecting heterogeneity in biological mechanisms of AD.

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Published In

GeroScience

DOI

EISSN

2509-2723

ISSN

2509-2715

Publication Date

February 2022

Volume

44

Issue

1

Start / End Page

265 / 280

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Pleiotropy
  • Alzheimer Disease
  • 3202 Clinical sciences
  • 3105 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kulminski, A. M., Loiko, E., Loika, Y., & Culminskaya, I. (2022). Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis. GeroScience, 44(1), 265–280. https://doi.org/10.1007/s11357-021-00484-1
Kulminski, Alexander M., Elena Loiko, Yury Loika, and Irina Culminskaya. “Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis.GeroScience 44, no. 1 (February 2022): 265–80. https://doi.org/10.1007/s11357-021-00484-1.
Kulminski AM, Loiko E, Loika Y, Culminskaya I. Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis. GeroScience. 2022 Feb;44(1):265–80.
Kulminski, Alexander M., et al. “Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis.GeroScience, vol. 44, no. 1, Feb. 2022, pp. 265–80. Epmc, doi:10.1007/s11357-021-00484-1.
Kulminski AM, Loiko E, Loika Y, Culminskaya I. Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis. GeroScience. 2022 Feb;44(1):265–280.

Published In

GeroScience

DOI

EISSN

2509-2723

ISSN

2509-2715

Publication Date

February 2022

Volume

44

Issue

1

Start / End Page

265 / 280

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Pleiotropy
  • Alzheimer Disease
  • 3202 Clinical sciences
  • 3105 Genetics