Cross-ancestry proteome-wide Mendelian randomization prioritizes 12 plasma protein candidates for breast cancer risk.

Xueyao Wu; Devika Godbole; Jacob Williams; Jayati Sharma; Jiyeon Choi; Zhonghua Liu; Peter Kraft; Haoyu Zhang

doi:10.64898/2026.05.04.26352055

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Cross-ancestry proteome-wide Mendelian randomization prioritizes 12 plasma protein candidates for breast cancer risk.

Xueyao Wu·Devika Godbole·Jacob Williams·Jayati Sharma·Jiyeon Choi·Zhonghua Liu·Peter Kraft·Haoyu Zhang

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Abstract

The plasma proteome provides a molecular bridge between genetic variation and disease risk, yet its contribution to breast cancer susceptibility across ancestries remains unclear. We conducted a proteome-wide Mendelian randomization (MR) study of 2,923 plasma proteins using cis-protein quantitative trait loci from 34,557 European participants in the UK Biobank Pharma Proteomics Project, integrated with genome-wide association studies of 156,901 breast cancer cases and 204,634 controls of European, East Asian, and African ancestries. Cross-ancestry meta-analysis identified 12 candidate proteins associated with breast cancer risk (P < 2.5×10-5), including six previously reported and six newly implicated in MR studies. DNPH1 showed cross-ancestry heterogeneity, with a risk-increasing association in European populations and a nominally inverse association in East Asian populations. CASP8, RALB, and USP28 displayed subtype-differentiated associations. Orthogonal validation provided variable support: six demonstrated strong evidence of statistical colocalization; four replicated in an independent European proteomic dataset (deCODE, n = 35,559); two replicated in an independent East Asian proteomic dataset (JCTF, n = 1,384); and four were supported by polygenic-score analyses in the ancestrally diverse All of Us cohort (9,250 cases, 214,857 controls). These findings prioritize a high-confidence subset of plasma proteins, including LRRC25, PARK7, and LRRC37A2, for future mechanistic and translational investigation.

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Mendelian randomization Plasma proteome breast cancer risk causal inference genetic epidemiology polygenic score proteogenomics Journal Article Preprint

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Xueyao Wu, Devika Godbole, Jacob Williams, Jayati Sharma, Jiyeon Choi, Zhonghua Liu, Peter Kraft, Haoyu Zhang. 2026-05-04. Cross-ancestry proteome-wide Mendelian randomization prioritizes 12 plasma protein candidates for breast cancer risk.. https://doi.org/10.64898/2026.05.04.26352055

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