Fig. 1

Overview of the study. (A) (i) Overlapping subjects are observed between AD genetic initiatives. (ii) There is no overlapping subject across ethnicities. Until now, trans-ethnic applications of PRS have been limited. We suspect that subject overlap within an ethnicity is one of the key factors to explain overestimated performances, which motivates this study. We divide PRS into two cases, where rPRS represents when the genetic information is provided and used as the discovery set and sPRS stands for the case when GWAS is pre-conducted and only summary statistics are provided. (B) For rPRS, overlapping subjects (n = 432) between ADSP and AMP-AD are identified, which breaks the independence assumption and causes the overestimation bias. For sPRS, the overlapping ratio cannot be examined by giving the summary statistics. However, the suspected inflation in the AD prediction performance (denoted by sPRS - rPRS) motivates further analysis of the scale effect of the datasets because IGAP has a larger number of samples. (C) (i) Two new variables, hypertension and height, from the UK Biobank database are introduced to compute the upper bounds of the scale effect. Hypertension and height have a higher heritability than AD. Thus, they act as the upper bounds for AD over PRS performances (shown in the QQ plot). (ii) In AD, the gap between sPRS and rPRS (area shaded in green) is attributable to either the overestimation bias or the scale effect of the sample size of the discovery set. Because UK Biobank consists of a larger number of samples (n = 342,318), the scale effect can be measured via computing the performance gains per sample unit. Cohort case counts and their percentages of the total were as follows: ADSP had 5687 (55.2%), AMP-AD had 696 (61.4%), IGAP had 17,008 (31.4%), and UK Biobank had 82,719 (24.2%)