Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E-04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E-05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E-24), five were located in the ETV5 gene (best SNP: rs1516725, p = 1E-24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E-09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E-08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

中文翻译：

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有证据表明，与刺猬信号有关的基因与躁郁症和高BMI都有关系。

患有双相情感障碍（BD）的患者显示出较高的肥胖率和2型糖尿病（T2D）发病率，但尚未对潜在的遗传决定因素和分子途径进行深入研究。我们使用大量公开可用的数据集，（1）使用MAGMA进行了基于基因的分析，以鉴定与BD和体重指数（BMI）或T2D相关的基因，并研究其功能富集；（2）使用Metasoft在BD和BMI以及BD和T2D之间进行了两次荟萃分析。使用药物基因相互作用数据库（DGIdb）评估了靶点的可药性。我们分别鉴定了与BD和BMI或BD和T2D显着相关的518和390个基因。经过多次测试校正后，共有52个基因和12个基因显着。对名义上重要的靶标进行的途径分析表明，与BD和BMI相关的基因在神经元细胞体基因本体论（GO）术语（p = 1.0E-04;误发现率（FDR）= 0.025）方面丰富，并且包括以下途径Hedgehog途径的信号传导（p = 4.8E-05，FDR = 0.02），而与BD和T2D相关的基因则没有特异性的富集。BD和BMI之间的荟萃分析确定了64种相关的单核苷酸多态性（SNP）。尽管其中大多数位于NPIPL1和SH2B1基因附近（最好SNP：rs4788101，p = 2.1E-24）以及在NPIPL1和SH2B1基因附近的基因间区域或16号位点，但其中有五个位于ETV5基因中（最好SNP： rs1516725，p = 1E-24），以前与BD和肥胖症有关，并且在RPGRIP1L基因中有一个（rs1477199，p = 5.7E-09），这也包括在《刺猬信号》中。BD和T2D之间的荟萃分析确定了六个重要的SNP，其中三个位于ALAS1中（最佳SNP：rs352165，p = 3.4E-08）。与BD和BMI相关的13个SNP，以及与BD和T2D相关的一个SNP，位于可药物基因组一部分的基因中。我们的结果支持BD和BMI之间共享遗传决定因素的假说，并指出与刺猬信号有关的基因是有希望的靶标。