In-silico functional analyses identify TMPRSS15-mediated intestinal absorption of lithium as a modulator of lithium response in bipolar disorder

David Stacey; Vijayaprakash Suppiah; Beben Benyamin; S Hong Lee; Elina Hyppönen

doi:10.1016/j.jad.2024.05.050

In-silico functional analyses identify TMPRSS15-mediated intestinal absorption of lithium as a modulator of lithium response in bipolar disorder

J Affect Disord. 2024 May 10:358:416-421. doi: 10.1016/j.jad.2024.05.050. Online ahead of print.

Authors

David Stacey¹, Vijayaprakash Suppiah², Beben Benyamin³, S Hong Lee³, Elina Hyppönen²

Affiliations

¹ Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia; University of South Australia Clinical and Health Sciences, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. Electronic address: david.stacey@unisa.edu.au.
² Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia; University of South Australia Clinical and Health Sciences, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
³ Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; University of South Australia Allied Health and Human Performance, Adelaide, South Australia, Australia.

PMID: 38735581
DOI: 10.1016/j.jad.2024.05.050

Abstract

Background: The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLi⁺Gen).

Methods: We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg.

Results: The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLi⁺Gen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium.

Limitations: Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLi⁺Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies.

Conclusions: The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption.

Keywords: Bipolar disorder; Functional genetics; GWAS; Intestinal absorption; Lithium; Lithium response.