Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease.
Florian Uellendahl-WerthCarlo MajOleg BorisovSimonas JuzenasEike Matthias WackerIsabella Friis JørgensenTim Alexander SteiertSaptarshi BejPeter M KrawitzPer HoffmannChristoph SchrammOlaf WolkenhauerKarina BanasikSoren BrunakStefan SchreiberTom Hemming KarlsenFranziska DegenhardtMarkus Maria NöthenAndre FrankeTrine FolseraasDavid EllinghausPublished in: Communications biology (2022)
Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies for 23 tissues of the gut-brain-axis using genome-wide association studies data sets (total 180,592 patients) for Crohn's disease, ulcerative colitis, primary sclerosing cholangitis, schizophrenia, bipolar disorder, major depressive disorder and attention-deficit/hyperactivity disorder. We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory ulcerative colitis) as shared susceptibility genes with transcriptome-wide significance both for Crohn's disease, ulcerative colitis and schizophrenia, largely explaining fine-mapped association signals at nearby genome-wide association study susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the gut-brain-axis. PPP3CA together with three further suggestive loci can be linked to calcineurin-related signaling pathways such as NFAT activation or Wnt.
Keyphrases
- bipolar disorder
- ulcerative colitis
- genome wide
- major depressive disorder
- single cell
- attention deficit hyperactivity disorder
- genome wide association study
- rna seq
- dna methylation
- genome wide association
- copy number
- gene expression
- end stage renal disease
- autism spectrum disorder
- case control
- ejection fraction
- electronic health record
- newly diagnosed
- white matter
- cell proliferation
- genome wide identification
- stem cells
- spinal cord
- chronic kidney disease
- working memory
- resting state
- deep learning
- protein kinase
- machine learning
- high throughput
- peritoneal dialysis
- risk factors
- big data
- artificial intelligence
- toll like receptor
- long non coding rna
- binding protein
- oxidative stress
- blood brain barrier
- nuclear factor