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.
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.
J Affect Disord. 2024 Aug 1;358:416-421. doi: 10.1016/j.jad.2024.05.050. Epub 2024 May 10.
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 (ConLiGen).
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.
The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLiGen 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.
Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLiGen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies.
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.
双相情感障碍患者对锂的治疗反应差异很大，具有多基因基础。全基因组关联研究调查了锂反应，确定了几个相关的基因座，但驱动这些关联的精确机制仍知之甚少。我们旨在确定最有可能的效应基因，并确定国际锂遗传学联合会（ConLiGen）确定的 21 号染色体上的基因间锂反应位点的潜在机制。
我们通过整合和综合来自多个公开可用的功能遗传数据集和数据库的信息，包括基因型-组织表达（GTEx）项目和 HaploReg，进行了计算机功能分析。
这项研究的结果突出了 TMPRSS15 作为 ConLiGen 锂反应位点最有可能的效应基因。TMPRSS15 编码肠激酶，这是一种胃肠道酶，负责将胰蛋白酶原转化为胰蛋白酶，从而帮助消化。来自人类和小鼠数据库的基于基因的查询以及对小型肠 RNA-seq 数据（GTEx）的共表达网络分析的一致发现表明 TMPRSS15 参与了肠道营养吸收的调节，包括钠和钾等离子，这可能延伸到锂。
尽管这项研究的结果表明 TMPRSS15 是 ConLiGen 锂反应位点最有可能的效应基因，但证据是间接的。因此，需要在适当设计的湿实验室研究中验证本研究的结论。
本研究的结果与 TMPRSS15 通过调节肠道锂吸收影响双相情感障碍患者锂治疗效果的模型一致。
