A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH AND RESULTS: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Identification of region-specific gene isoforms in the human brain using long-read transcriptome sequencing.

In neurological and neuropsychiatric diseases, different brain regions are affected, and differences in gene expression patterns could potentially explain this mechanism. However, limited studies have precisely explored gene expression in different regions of the human brain. In this study, we performed long-read RNA sequencing on three different brain regions of the same individuals: the cerebellum, hypothalamus, and temporal cortex. Despite stringent filtering criteria excluding isoforms predicted to be artifacts, over half of the isoforms expressed in multiple samples across multiple regions were found to be unregistered in the GENCODE reference. We then especially focused on genes with different major isoforms in each brain region, even with similar overall expression levels, and identified that many of such genes including GAS7 might have distinct roles in dendritic spine and neuronal formation in each region. We also found that DNA methylation might, in part, drive different isoform expressions in different regions. These findings highlight the significance of analyzing isoforms expressed in disease-relevant sites.