Genome-wide association studies of polygenic risk score-derived phenotypes may lead to inflated false positive rates

arising from: C. Gouveia et al.; Scientific Reports https://doi.org/10.1038/s41598-022-12391-2 (2022).

Gouveia and colleagues (2022)¹ conducted a genome-wide association study (GWAS) of a polygenic risk score (PRS)-derived phenotype (N = 37,784), in which they identified 246 independent loci and 473 lead SNPs. This is an enormous increase compared to the most recent and largest GWAS of AD² (N = 1,126,563), which identified 38 loci. Here we show that the applied approach by Gouveia and colleagues may lead to an inflated false positive rate.

In this approach, beta-estimates from a recent GWAS of Alzheimer’s disease (AD)³ were used to construct PRSs in the European UK Biobank⁴ sample, using pruning and thresholding⁵ with a p-value threshold of 5%. Next, a new case–control phenotype was constructed based on the bottom and top 5% of the PRS distribution, removing 90% of their…