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Cited by 45Dementia and Cognitive Impairment ResearchGenetic Associations and EpidemiologyAlzheimer's disease research and treatments

Pervasive biases in proxy genome-wide association studies based on parental history of Alzheimer’s disease

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Wu, Yuchang, Sun, Zhongxuan, Zheng, Qinwen, Miao, Jiacheng, Dorn, Stephen, Mukherjee, Shubhabrata, Fletcher, Jason M., Lu, Qiongshi·2024·Nature Genetics
DOI 10.1038/s41588-024-01963-9PMC PMC11929606
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Abstract

Almost every recent Alzheimer's disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and nonrandom participation in parental illness surveys, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that the current AD GWAX provide highly misleading genetic correlations between AD risk and higher education, which subsequently affects a variety of genetic epidemiological applications involving AD and cognition. Our study sheds light on potential issues in the design and analysis of middle-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

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Authors
Wu, Y., Sun, Z., Zheng, Q., Miao, J., Dorn, S., Mukherjee, S., Fletcher, J. M., & Lu, Q.
Affiliations
  • University of Wisconsin–Madison (US)
  • University of Washington (US)
Corresponding author
Lu, Qiongshi
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2024-11-04
Volume
56
Issue
12
Pages
2696-2703
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-024-01963-9
PMC
PMC11929606
OpenAlex
W4404045822
Cited by
45
References
50
Citations by year
2026: 23 · 2025: 21 · 2024: 1
FWCI
13.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (P30 AG017266, R21 AG085162)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, survivorship bias, genetic correlation, higher education, cognitive function, biobank cohort
MeSH terms
Alzheimer Disease, Female, Humans, Male, Middle Aged, Parents, Phenotype, Bias, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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