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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
背景：双相情感障碍患者对锂的治疗反应是高度可变的，并且具有多基因基础。调查锂反应的全基因组关联研究已经确定了几个相关基因座，尽管驱动这些关联的确切机制知之甚少。我们旨在优先考虑最有可能的效应基因，并确定国际锂遗传学协会（ConLiGen）鉴定的21号染色体上基因间锂反应基因座的潜在机制。
方法：我们通过整合和合成来自几个公开的功能遗传数据集和数据库（包括基因型-组织表达（GTEx）项目和HaploReg）的信息进行了计算机功能分析。
结果：这项研究的发现强调了TMPRSS15是ConLiGen锂反应基因座上最可能的效应基因。TMPRSS15编码肠激酶，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中基于基因的查找以及小肠RNA-seq数据（GTEx）的共表达网络分析的融合发现表明TMPRSS15参与了肠道营养吸收的调节，包括离子如钠和钾，可能延伸到锂。
结论：尽管这项研究的结果表明，TMPRSS15是ConLiGen锂反应基因座上最有可能的效应基因，证据是间接的。因此，本研究的结论需要在适当设计的湿实验室研究中进行验证.
结论：这项研究的结果与TMPRSS15通过调节肠道锂吸收影响双相情感障碍患者锂治疗疗效的模型一致。
方法：我们通过整合和合成来自几个公开的功能遗传数据集和数据库（包括基因型-组织表达（GTEx）项目和HaploReg）的信息进行了计算机功能分析。
结果：这项研究的发现强调了TMPRSS15是ConLiGen锂反应基因座上最可能的效应基因。TMPRSS15编码肠激酶，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中基于基因的查找以及小肠RNA-seq数据（GTEx）的共表达网络分析的融合发现表明TMPRSS15参与了肠道营养吸收的调节，包括离子如钠和钾，可能延伸到锂。
结论：尽管这项研究的结果表明，TMPRSS15是ConLiGen锂反应基因座上最有可能的效应基因，证据是间接的。因此，本研究的结论需要在适当设计的湿实验室研究中进行验证.
结论：这项研究的结果与TMPRSS15通过调节肠道锂吸收影响双相情感障碍患者锂治疗疗效的模型一致。
