Multi-ancestry sequencing-based genome-wide association study of C-reactive protein in 513,273 genomes

Hongru Li, Jingyi Zhao, Jinglan Dai, Dongfang You, Yang Zhao, David C. Christiani, Feng Chen () and Sipeng Shen ()
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Hongru Li: Nanjing Medical University
Jingyi Zhao: Nanjing Medical University
Jinglan Dai: Nanjing Medical University
Dongfang You: Nanjing Medical University
Yang Zhao: Nanjing Medical University
David C. Christiani: Harvard University
Feng Chen: Nanjing Medical University
Sipeng Shen: Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract C-reactive protein (CRP) serves as a pivotal marker of systemic inflammation, yet its genetic architecture has predominantly been explored within European populations. Our multi-ancestry sequencing-based genome-wide association study (seqGWAS) meta-analysis encompasses 447,369 Europeans, 10,389 Africans, 9685 Asians, and 9200 Hispanics in the discovery set, and 23,521 Europeans, 7160 Africans, 771 Asians, and 5178 Hispanics in the replication set. We identify 113 independent association signals (Pdiscovery ≤ 5 × 10−9 and Preplication ≤ 0.05), including 21 loci that passed the conditional analysis, among which 3 are European-specific. Cross ancestry fine-mapping pinpoints 19 of 113 independent signals within the 95% credible set. Functional annotation reveals significant enrichment in blood tissue, H3K27me3 histone marks, and exonic regions. Leveraging the Polygenic Priority Score (PoPS) and gene-based analyses, we implicate 151 genes as potential regulators of CRP levels, 55 of which have not been previously reported. Among these, 17 genes and four proteins show causal evidence or strong colocalization with CRP-related pathologies.

Date: 2025
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DOI: 10.1038/s41467-025-59155-w

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