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<p>Most genetic variants influence complex traits by affecting gene regulation. Yet, despite comprehensive catalogs of molecular quantitative trait loci (QTLs), linking trait-associated variants to biological functions remains difficult. By re-analyzing large maps of protein QTLs (pQTLs), we found that genes with <i>trans</i>-pQTLs but no <i>cis</i>-pQTLs are under strong selective constraints and are particularly informative in interpreting genome-wide association study (GWAS) loci. We observed that <i>trans</i>-pQTLs and their target proteins are frequently involved in protein–protein interactions (PPIs). Notably, <i>trans</i>-pQTLs are enriched in missense variants and at PPI interfaces, suggesting a key role of PPIs in the <i>trans</i>-regulation of proteome. Using PPI annotations to guide <i>trans</i>-pQTL mapping, we identified 17,662 <i>trans</i>-pQTLs affecting 961 PPI clusters after accounting for blood cell composition effects. These <i>trans</i>-pQTLs colocalized with 36% GWAS loci per trait on average for 27 complex traits, helping in many cases to link GWAS loci to cellular function. Finally, we identified <i>trans</i>-pQTL effects at multiple autoimmune GWAS loci that converge to the same PPIs, pinpointing protein complexes and signaling pathways that show promising therapeutic target potential.</p>

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Protein–protein interactions shape trans-regulatory impact of genetic variation on protein expression and complex traits

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Jinghui Li,
  • Yang I. Li,
  • Xuanyao Liu

摘要

Most genetic variants influence complex traits by affecting gene regulation. Yet, despite comprehensive catalogs of molecular quantitative trait loci (QTLs), linking trait-associated variants to biological functions remains difficult. By re-analyzing large maps of protein QTLs (pQTLs), we found that genes with trans-pQTLs but no cis-pQTLs are under strong selective constraints and are particularly informative in interpreting genome-wide association study (GWAS) loci. We observed that trans-pQTLs and their target proteins are frequently involved in protein–protein interactions (PPIs). Notably, trans-pQTLs are enriched in missense variants and at PPI interfaces, suggesting a key role of PPIs in the trans-regulation of proteome. Using PPI annotations to guide trans-pQTL mapping, we identified 17,662 trans-pQTLs affecting 961 PPI clusters after accounting for blood cell composition effects. These trans-pQTLs colocalized with 36% GWAS loci per trait on average for 27 complex traits, helping in many cases to link GWAS loci to cellular function. Finally, we identified trans-pQTL effects at multiple autoimmune GWAS loci that converge to the same PPIs, pinpointing protein complexes and signaling pathways that show promising therapeutic target potential.