Authors: Rodrigo Araujo Sequeira Barreiro, Tatiana Ferreira de Almeida, Catarina dos Santos Gomes, Frederico Monfardini, Allysson Allan de Farias, Gabriela Chiuffa Tunes, Gabriel Mesquita de Souza, Etienne Duim, Jaqueline de Sá Correia, Antonio Victor Campos Coelho, Marcel Pinheiro Caraciolo, Yeda Aparecida Oliveira Duarte, Mayana Zatz, Edson Amaro, João Bosco Oliveira, Bárbara Domingues Bitarello, Helena Brentani, Michel Satya Naslavsky
Source: The Journal of Molecular Diagnostics, DOI:10.1016/j.jmoldx.2024.06.002, July 2024
Type of Publication: Article
Abstract: Polygenic risk scores (PRSs) for breast cancer have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium and differences in variant frequency (allele frequency differences). Thus, locally sourced population-based phenotypic and genomic data sets are essential to assess the validity of PRSs derived from signals detected across populations. Here, we assess the transferability of a breast cancer PRS composed of 313 risk variants (313-PRS) in a Brazilian trihybrid admixed ancestries (European, African, and Native American) whole-genome sequenced cohort, the Rare Genomes Project. We computed 313-PRS in the Rare Genomes Project (n = 853) using the UK Biobank (UKBB; n = 264,307) as reference. We show that although the Brazilian cohorts have a high European ancestry (EA) component, with allele frequency differences and to a lesser extent linkage disequilibrium patterns similar to those found in EA populations, the 313-PRS distribution is inflated when compared with that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. Interestingly, we find that case controls lead to equivalent predictive power when compared with UKBB-EA samples with area under the receiver operating characteristic curve values of 0.66 to 0.62 compared with 0.63 for UKBB.
