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Using family health history as proxy phenotype has become a common approach in genome-wide association studies (GWAS) of Alzheimer's disease (AD). This approach leverages large samples in population biobanks where most mid-aged participants do not have any AD diagnosis. However, methodological issues in GWAS-by-proxy (GWAX) and quality of its association results have not been carefully investigated. We performed GWAX on parental AD history in UK Biobank (N = 48,031 proxy cases and 315,286 controls). AD GWAS and GWAX showed drastically different genetic correlations with several other complex traits especially cognitive abilities, revealing substantial survival bias and non-random over- and under-reporting of family member's illnesses. Adjusting for parental age in GWAX substantially reduced but did not fully remove the genetic correlation of AD and higher education (rg=0.013, p=0.67), hinting at additional unaccounted factors in the current GWAX practice. We also provide evidence that genetic correlation between family health history awareness and education (rg=0.285, p=1.4e-10) leads to these biases in GWAX associations.
Yuchang Wu, University of Wisconsin-Madison
Zhongxuan Sun, University of Wisconsin-Madison
Jason M. Fletcher, University of Wisconsin-Madison
Qiongshi Lu, University of Wisconsin-Madison