Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic and calcium signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers and antiepileptics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

“…Further PTV enrichment was observed in the top 50 genes over the FDR < 5% set; OR = 2.02, P = 8.14 × 10 −7 , but this significant enrichment was not observed as we moved down through the genes displaying ultra-rare damaging case-control enrichment in SCHEMA (genes 51-100; OR = 0.936, P = 0.680, genes 101-150; OR = 1.03, P = 0.794, genes 151-200; OR = 1.07, P = 0.686). We also did not observe PTV enrichment of ultra-rare damaging variation in the recently fine-mapped schizophrenia genes published by the PGC ( 11 ): OR = 1.10, P = 0.178.…”

“…To date, GWAS meta-analysis of common SNPs have now identified 64 independent loci that contribute to BD susceptibility, implicating genes encoding ion channels, neurotransmitter transporters, and synaptic and calcium signalling pathways ( 3, 11 ). Evidence of rare variation on BD risk, however, remains inconclusive as sample sizes are substantially smaller than GWAS.…”

Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder

“…For example, they include four calcium channels ( CACNA1C, CACNA2D4, CACNB2 , and CACNG8 ), three glutamate receptors (GRIK2, GRIN2A , and GRM8 ), four GABA receptors ( GABRA5, GABRG3, GABRG3 , and GABRP ), and nine potassium channels ( KCNA1, KCNA4, KCNA7, KCNAB2, KCNAB2, KCND3, KCND3, KCNE1 , and KCNG2 ). A recent GWAS showed enrichment of GWAS signals in calcium signaling genes and genes expressed in neurons 69 . The current finding of DNA methylation changes in ion channels, including calcium channels, sheds light on the potential roles of these channels in nonneurons, such as oligodendrocytes, microglia, and astrocytes, in BD.…”

Feasibility and application of polygenic score analysis to the morphology of human induced pluripotent stem cells

“…As such, the polygenic score may (in part) be capturing variability in cell-extracellular matrix adhesion. Cell-extracellular matrix adhesion is fundamental to cell crawling and axon guidance [41][42][43] , which has also been implicated in psychiatric disorders 15,[19][20][21] . The composition of the extracellular matrix, and increased adhesion of cells to the matrix, has been shown to increase neurite extension in neurons 42,43 , to stimulate gyrification in the developing human neocortex 44 , and to promote branching and migration of neurons 42,45 , among other roles 42 .…”

“…It also is feasible that the polygenic components studied may affect the morphology of iPSCs directly. For example, genes involved in neuronal morphology have been implicated in numerous GWAS of psychiatric disorders 15,[19][20][21] . While strongest in neurons, these effects may also be apparent in the morphology of cells more generally, particularly in iPSCs, whose cellular fate is undetermined.…”