Cross-ancestry proteome-wide Mendelian randomization of plasma proteins and breast cancer susceptibility

Cross-ancestry proteome-wide Mendelian randomization linked breast cancer susceptibility to 12 plasma proteins (Bonferroni P < 0.05/1,971), prioritizing LRRC25, PARK7, and LRRC37A2.

• Why it matters: Inherited breast cancer risk may be mediated by circulating proteins, but proteome-wide causal evidence across ancestries has been limited, limiting interpretable and equitable target discovery.
• What they did: Using cis-protein quantitative trait loci for 1,962 proteins from 34,557 European-ancestry UK Biobank Pharma participants, the study performed ancestry-specific MR against GWAS with 156,901 cases and 204,634 controls across European, East Asian, and African ancestries.
• The result: Twelve proteins met significance in fixed-effects cross-ancestry meta-analysis, with heterogeneity for DNPH1 and cross-subtype heterogeneity for CASP8, RALB, and USP28, plus colocalization (PPH4 ≥ 0.80) and replication/All of Us protein polygenic score support for subsets.

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