Growing evidence has revealed the associations between telomere length and diseases; however, the mechanisms behind these links are not fully understood. In this study, by applying proteome-wide Mendelian randomisation (MR), multiple sensitivity analyses, colocalization, single-cell RNA-sequencing, and mediation analysis, the potential mechanisms that link 4,907 plasma proteins, telomere length, and 8 diseases were identified. Following MR analysis for the effects of plasma protein levels on telomere length, 34 proteins were found to be causally related to telomere length. Among these, 8 proteins (PSMB4, PARP1, GDI2, MAX, GMPR2, ARPC1B, ATOX1, and NUDT5) were found to be well colocalized with telomere length (posterior probability >80%). 21 mediation pairs were revealed for the indirect effect of circulating proteins on 8 diseases via telomere length. Furthermore, 35 proteins, including CD8A, were found to be influenced by telomere length among 4,907 proteins. No significant mediation pairs for circulating proteins that mediate the effects of telomere length on disease have been identified. Overall, our study provided insights into understanding the biology of telomeres and prioritized the identified proteins as prospective intervention targets for the disease.

The authors have declared no competing interest.

This study did not receive any funding

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