Genetic association and Mendelian randomization for hypothyroidism highlight immune molecular mechanisms

Samuel Mathieu; Mewen Briend; Erik Abner; Christian Couture; Zhonglin Li; Yohan Bossé; Sébastien Thériault; Tõnu Esko; Benoit J Arsenault; Patrick Mathieu

doi:10.1016/j.isci.2022.104992

Genetic association and Mendelian randomization for hypothyroidism highlight immune molecular mechanisms

iScience. 2022 Aug 20;25(9):104992. doi: 10.1016/j.isci.2022.104992. eCollection 2022 Sep 16.

Authors

Samuel Mathieu^{1

2}, Mewen Briend^{1

2}, Erik Abner³, Christian Couture^{1

2}, Zhonglin Li², Yohan Bossé^{2

4}, Sébastien Thériault^{2

5}, Tõnu Esko³, Benoit J Arsenault^{1

2

6}, Patrick Mathieu^{1

2

7}

Affiliations

¹ Genomic Medecine and Molecular Epidemiology Laboratory, Quebec Heart and Lung Institute, Laval University, Québec, QC, Canada.
² Quebec Heart and Lung Institute, Laval University, Québec, QC, Canada.
³ Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴ Department of Molecular Medicine, Laval University, Québec, QC, Canada.
⁵ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec, QC, Canada.
⁶ Department of Medicine, Laval University, Québec, QC, Canada.
⁷ Department of Surgery, Laval University, Québec, QC, Canada.

Abstract

We carried out a genome-wide association analysis including 51,194 cases of hypothyroidism and 443,383 controls. In total, 139 risk loci were associated to hypothyroidism with genes involved in lymphocyte function. Candidate genes associated with hypothyroidism were identified by using molecular quantitative trait loci, colocalization, and enhancer-promoter chromatin looping. Mendelian randomization (MR) identified 42 blood expressed genes and circulating proteins as candidate causal molecules in hypothyroidism. Drug-gene interaction analysis provided evidence that immune checkpoint and tyrosine kinase inhibitors used in cancer therapy increase the risk of hypothyroidism. Hence, integrative mapping and MR support that expression of genes and proteins enriched in lymphocyte function are associated with the risk of hypothyroidism and provide genetic evidence for drug-induced hypothyroidism and identify actionable potential drug targets.

Keywords: Clinical genetics; Genomics; Molecular genetics.