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Pervasive biases in proxy GWAS based on parental history of Alzheimer's disease.

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 non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current AD GWAX provide highly misleading genetic correlations between AD risk and higher education which subsequently affects a variety of genetic epidemiologic applications involving AD and cognition. Our study sheds important light on the design and analysis of mid-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

SUBMITTER: Wu Y

PROVIDER: S-EPMC10614766 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Pervasive biases in proxy GWAS based on parental history of Alzheimer's disease.

Wu Yuchang Y Sun Zhongxuan Z Zheng Qinwen Q Miao Jiacheng J Dorn Stephen S Mukherjee Shubhabrata S Fletcher Jason M JM Lu Qiongshi Q

bioRxiv : the preprint server for biology 20231017

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 non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current A ...[more]

PMID: 37904974

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