Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.

Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.

Motivation Population stratification (PS) is a major confounder in genome-wide association studies (GWAS) and can lead to false-positive associations. To adjust for PS, principal component analysis (PCA)-based ancestry prediction has been widely used. Simple projection (SP) based on principal component loadings and the recently developed data augmentation, decomposition and Procrustes (ADP) transformation, such as LASER and TRACE, are popular methods for predicting PC scores. However, the predicted PC scores from SP can be biased toward NULL. On the other hand, ADP has a high computation cost because it requires running PCA separately for each study sample on the augmented dataset. Results We develop and propose two alternative approaches: bias-adjusted projection (AP) and online ADP (OADP). Using random matrix theory, AP asymptotically estimates and adjusts for the bias of SP. OADP uses a computationally efficient online singular value decomposition algorithm, which can greatly reduce the computation cost of ADP. We carried out extensive simulation studies to show that these alternative approaches are unbiased and the computation speed can be 16–16 000 times faster than ADP. We applied our approaches to the UK Biobank data of 488 366 study samples with 2492 samples from the 1000 Genomes data as the reference. AP and OADP required 0.82 and 21 CPU hours, respectively, while the projected computation time of ADP was 1628 CPU hours. Furthermore, when inferring sub-European ancestry, SP clearly showed bias, unlike the proposed approaches. Availability and implementation The OADP and AP methods, as well as SP and ADP, have been implemented in the open-source Python software FRAPOSA, available at github.com/daviddaiweizhang/fraposa. Contact leeshawn@umich.edu Supplementary information Supplementary data are available at Bioinformatics online.