Novel Causal Plasma Proteins for Hypothyroidism: A Large-scale Plasma Proteome Mendelian Randomization Analysis

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Proteomics

Background:

• Hypothyroidism has several known risk proteins, but many plasma proteins remain untested for their role.
• Understanding novel causal plasma proteins is crucial for elucidating hypothyroidism mechanisms.

Purpose of the Study:

• To identify novel causal plasma proteins for hypothyroidism using Mendelian randomization (MR).
• To explore potential mechanisms underlying hypothyroidism through plasma protein associations.

Main Methods:

• A large-scale Mendelian randomization (MR) analysis of plasma proteome data (2297 proteins) using protein quantitative trait loci (pQTLs).
• MR analyses were performed across four pQTL groups, with significant proteins validated in independent cohorts.
• Colocalization and enrichment analyses were conducted on identified proteins.

Main Results:

• Thirty-one proteins were initially identified, with 13 validated in a separate cohort.
• Nine proteins were identified as risk factors and four as protective factors for hypothyroidism.
• Specific proteins like POGLUT1 and interferon (IFN)-lambda-1 showed strong colocalization with hypothyroidism-related genetic data.

Conclusions:

• Thirteen plasma proteins were validated as associated with hypothyroidism.
• The study expands the understanding of causal proteins for hypothyroidism and their relationship with plasma proteins.
• Identified proteins may serve as early screening biomarkers for hypothyroidism.