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Cited by 51Genetic Associations and EpidemiologyDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Mendelian randomization highlights significant difference and genetic heterogeneity in clinically diagnosed Alzheimer’s disease GWAS and self-report proxy phenotype GWAX

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Liu, Haijie, Hu, Yang, Zhang, Yan, Zhang, Haihua, Gao, Shan, Wang, Longcai, Wang, Tao, Han, Zhifa +2 more·2022·Alzheimer's Research & Therapy
DOI 10.1186/s13195-022-00963-3PMC PMC8800228
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Abstract

Background: Until now, Mendelian randomization (MR) studies have investigated the causal association of risk factors with Alzheimer’s disease (AD) using large-scale AD genome-wide association studies (GWAS), GWAS by proxy (GWAX), and meta-analyses of GWAS and GWAX (GWAS+GWAX) datasets. However, it currently remains unclear about the consistency of MR estimates across these GWAS, GWAX, and GWAS+GWAX datasets. Methods: Here, we first selected 162 independent educational attainment genetic variants as the potential instrumental variables (N = 405,072). We then selected one AD GWAS dataset (N = 63,926), two AD GWAX datasets (N = 314,278 and 408,942), and three GWAS+GWAX datasets (N = 388,324, 455,258, and 472,868). Finally, we conducted a MR analysis to evaluate the impact of educational attainment on AD risk across these datasets. Meanwhile, we tested the genetic heterogeneity of educational attainment genetic variants across these datasets. Results: In AD GWAS dataset, MR analysis showed that each SD increase in years of schooling (about 3.6 years) was significantly associated with 29% reduced AD risk (OR=0.71, 95% CI: 0.60–0.84, and P=1.02E−04). In AD GWAX dataset, MR analysis highlighted that each SD increase in years of schooling significantly increased 84% AD risk (OR=1.84, 95% CI: 1.59–2.13, and P=4.66E−16). Meanwhile, MR analysis suggested the ambiguous findings in AD GWAS+GWAX datasets. Heterogeneity test indicated evidence of genetic heterogeneity in AD GWAS and GWAX datasets. Conclusions: We highlighted significant difference and genetic heterogeneity in clinically diagnosed AD GWAS and self-report proxy phenotype GWAX. Our MR findings are consistent with recent findings in AD genetic variants. Hence, the GWAX and GWAS+GWAX findings and MR findings from GWAX and GWAS+GWAX should be carefully interpreted and warrant further investigation using the AD GWAS dataset.

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References 52 · Cited by 51

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Authors
Liu, H., Hu, Y., Zhang, Y., Zhang, H., Gao, S., Wang, L., Wang, T., Han, Z., Sun, B.-L., & Liu, G.
Affiliations
  • Capital Medical University (CN)
  • Harbin Institute of Technology (CN)
  • Weifang Medical University (CN)
  • Chinese Institute for Brain Research (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author
Liu, Guiyou
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-01-28
Volume
14
Issue
1
Pages
17-17
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-022-00963-3
PMC
PMC8800228
OpenAlex
W4210363323
Cited by
51
References
52
Citations by year
2026: 6 · 2025: 19 · 2024: 11 · 2023: 10 · 2022: 5
FWCI
7.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
national natural science foundation of china (82071212, and 81901181)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, educational attainment, years of schooling, genetic heterogeneity, instrumental variables, causal risk factors, Alzheimer's disease risk
MeSH terms
Alzheimer Disease, Humans, Phenotype, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis, Self Report

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