Unit of Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
Transl Psychiatry. 2019 Nov 21;9(1):315. doi: 10.1038/s41398-019-0652-x.
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.
患者的双相情感障碍（BD）表现出更高的频率肥胖和 2 型糖尿病（T2D），但潜在的遗传决定因素和分子途径尚未得到很好的研究。使用大型公共可用数据集，我们（1）进行了一项基于基因的分析，使用 MAGMA 来识别与 BD 和体重指数（BMI）或 T2D 相关的基因，并研究了它们的功能富集；以及（2）使用 Metasoft 对 BD 与 BMI 之间，以及 BD 与 T2D 之间进行了两项荟萃分析。使用药物基因相互作用数据库（DGIdb）评估了靶标可药性。我们分别鉴定了 518 个和 390 个与 BD 和 BMI 或 BD 和 T2D 显著相关的基因。经过多次测试校正后，共有 52 个和 12 个基因分别显著。对名义上显著的靶标进行的途径分析表明，与 BD 和 BMI 相关的基因富集了神经元细胞体基因本体论（GO）术语（p=1.0E-04；错误发现率（FDR）=0.025）和不同的途径，包括 Hedgehog 信号通路（p=4.8E-05，FDR=0.02），而与 BD 和 T2D 相关的基因则没有特定的富集。BD 与 BMI 之间的荟萃分析确定了 64 个相关的单核苷酸多态性（SNP）。虽然大多数 SNP 位于基因间区域或 16 号染色体上靠近 NPIPL1 和 SH2B1 基因的位置（最佳 SNP：rs4788101，p=2.1E-24），但有 5 个 SNP 位于 ETV5 基因（最佳 SNP：rs1516725，p=1E-24），该基因先前与 BD 和肥胖均相关，1 个 SNP 位于 RPGRIP1L 基因（rs1477199，p=5.7E-09），该基因也包含在 Hedgehog 信号通路中。BD 与 T2D 之间的荟萃分析确定了 6 个显著的 SNP，其中 3 个位于 ALAS1 基因（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 1 个 SNP，位于药物基因组学部分的基因中。我们的结果支持 BD 和 BMI 之间存在共同遗传决定因素的假设，并指出与 Hedgehog 信号相关的基因是有前途的靶点。
