Objective  To evaluate the causal relationship between plasma proteins and restless legs syndrome (RLS) by proteome-wide Mendelian randomization (MR) and to explore new therapeutic targets for RLS.

Methods  Genome-wide association studies (GWAS) data of plasma proteins were obtained from the UK Biobank, and GWAS data of RLS were extracted from the FinnGen R11 database. Colocalization analysis was performed to identify the common causal variants between plasma proteins and RLS.

Results  MR analysis showed that plasma proteins ASPSCR1 [OR=0.678, 95%CI (0.544, 0.847)] and C1QTNF5 [OR=0.526, 95%CI (0.367, 0.752)] had a protective effect on RLS; plasma proteins KRT19 [OR=1.769, 95%CI (1.283, 2.439)] and LAT2 [OR=5.536, 95%CI (2.206, 13.893)] were associated with the increased risk of RLS. Colocalization analysis showed that among the 4 plasma proteins, LAT2 had a strong causal variation relationship, while ASPSCR1, C1QTNF5, and KRT19 had a moderate causal variation relationship. The protein functional network suggested that protein-associated genes related to RLS were significantly enriched in sugar transmembrane transporter activity, carbohydrate transmembrane transport activity, and Fc receptor signaling pathway.

Conclusion  This study identifies the causal relationship between 4 plasma proteins and RLS, which provides potential therapeutic targets for the treatment of RLS, but further studies are needed to confirm it.

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