Identification of SLC25A37 as a major depressive disorder risk gene

Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders, but the genetic etiology remains largely unknown. We performed a meta-analysis (14,543 MDD cases and 14,856 controls) through combining the GWAS data from the Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium and the CONVERGE consortium and identified seven SNPs (four of them located in the downstream of SCL25A37) that showed suggestive associations (P < 5.0 × 10⁻⁷) with MDD. Systematic integration (Sherlock integrative analysis) of brain eQTL and GWAS meta-analysis identified SCL25A37 as a novel MDD risk gene (P = 2.22 × 10⁻⁶). A cis SNP (rs6983724, ∼28 kb downstream of SCL25A37) showed significant association with SCL25A37 expression (P = 1.19 × 10⁻⁹) and suggestive association with MDD (P = 1.65 × 10⁻⁷). We validated the significant association between rs6983724 and SCL25A37 expression in independent expression datasets. Finally, we found that SCL25A37 is significantly down-regulated in hippocampus and blood of MDD patients (P = 3.49 × 10⁻³ and P = 2.66 × 10⁻¹³, respectively). Our findings implicate that the SCL25A37 is a MDD susceptibility gene whose expression may influence MDD risk. The consistent down-regulation of SCL25A37 in MDD patients in three independent samples suggest that SCL25A37 may be used as a potential biomarker for MDD diagnosis. Further functional characterization of SCL25A37 may provide a potential target for future therapeutics and diagnostics.     

Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing

Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C‐X‐C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C‐X‐C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5⁺ and CXCL13⁺ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS‐associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5⁺ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19⁺CD27⁺immunoglobulin (Ig)D⁺ marginal zone (P < 0·001), CD19⁺CD27⁺IgD^– memory (P < 0·05) and CD27‐IgD double‐negative (P < 0·01) B cells and CD4⁺CXCR3^–CCR6⁺ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5⁺ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5⁺ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.     

Retinal ciliopathies through the lens of Bardet-Biedl Syndrome: Past,present and future

The primary cilium is a highly specialized and evolutionary conserved organelle in eukaryotes that plays a significant role in cell signaling and trafficking. Over the past few decades tremendous progress has been made in understanding the physiology of cilia and the underlying pathomechanisms of various ciliopathies. Syndromic ciliopathies consist of a group of disorders caused by ciliary dysfunction or abnormal ciliogenesis. These disorders have multiorgan involvement in addition to retinal degeneration underscoring the ubiquitous distribution of primary cilia in different cell types. Genotype-phenotype correlation is often challenging due to the allelic heterogeneity and pleiotropy of these disorders. In this review, we discuss the clinical and genetic features of syndromic ciliopathies with a focus on Bardet-Biedl syndrome (BBS) as a representative disorder. We discuss the structure and function of primary cilia and their role in retinal photoreceptors. We describe the progress made thus far in understanding the functional and genetic characterization including expression quantitative trait locus (eQTL) analysis of BBS genes. In the future directions section, we discuss the emerging technologies, such as gene therapy, as well as anticipated challenges and their implications in therapeutic development for ciliopathies.