Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

Abstract

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.

Applying dimensional psychopathology: transdiagnostic associations among regional homogeneity, leptin and depressive symptoms

“…Moreover, these differences were graded, with greatest alterations in SCZ, followed by BPD, and then MDD, which mirror the clinical severity and prognosis of three disorders. Our current findings are in line with previous GWAS 43 and neuroimaging studies 17 , 44 – 46 . Taken together, this study provides critical insights into the biological basis of SCZ, BPD and MDD from a transdiagnostic perspective.…”

Phenotype integration improves power and preserves specificity in biobank-based genetic studies of MDD

“…This hit overlaps the gene NEGR1 (top SNP rs1194283, OR = 1.05, SE = 0.0065, P = 6.71x10 -13 , Figure 3G), which has been identified as an MDD risk locus in multiple GWAS studies with varying phenotyping approaches 2,4,6,[29][30][31] . Intriguingly, this locus also has replicated associations with body mass index and obesity in diverse populations [32][33][34][35] , suggesting it may act on MDD through a metabolic pathway that is independent of neuroticism. We also tested adjusting for each of the other top 10 factors.…”

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference

“…GRIN2B variation has also been implicated in bipolar disorder, which has elevated impulsivity and risk taking 72 in the Chinese Han 73 and Ashkenazi Jewish 74 populations. Other potential genes include MAP2K5 , which was associated with bipolar disorder 75 , and many genes, such as LIN28B, MSI2, HIP1R implicated in schizophrenia (Table S2).…”