Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese

Background and objectivesIgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy.Design, setting, participants, & measurementsWe performed a two-stage exome chip–based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored.ResultsWe identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (Pmeta<5×10−5) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, were involved in IgA nephropathy.ConclusionsFive novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.

Molecular landscape of pelvic organ prolapse provides insights into disease etiology and clues towards putative novel treatments

BackgroundPelvic organ prolapse (POP) represents a major health care burden in women but its underlying pathophysiological mechanisms have not been elucidated.ObjectiveTo integrate the results from a large scale exome chip study with published genetic and expression data into a molecular landscape of POP.Design, setting, and participantsThe exome chip study was conducted in 526 women with POP and 960 healthy controls. To corroborate the findings, we analysed differential gene expression data from 12 POP patients. Vaginal fibroblasts from 4 women with POP were used to test the effect of the anti-diabetic drug metformin.Outcome measurements and statistical analysisThe exome chip study used a case-control design to identify single nucleotide variants (SNVs) associated with POP after Bonferroni correction. The molecular landscape was built using the UniProt and PubMed databases to identify functional interactions between the POP candidate genes/proteins. We performed enrichment and upstream regulator analyses of the differentially expressed genes. The effect of metformin in fibroblasts was assessed using one-sample t-test.Results and limitationsWe found significant association between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into a molecular landscape, together with 37 other POP candidate molecules and two POP-implicated microRNAs. This landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes - epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function - that are regulated by sex hormones and TGFB1. Based on the landscape, we predicted and showed that metformin alters gene expression in fibroblasts of POP patients in a beneficial direction. The main limitation of our study is that we have no independent replication of the exome chip results.ConclusionsThe integrated molecular landscape of POP that we built provides insights into the biological processes underlying the disease and clues towards novel treatments.Patient summaryWe reported the first exome chip study of POP and combined the genes identified in this study with other data from the literature to build a ‘molecular landscape’ of POP. This landscape will advance our understanding of the disease and may lead to novel treatments.

Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation

Key Points We conducted the first exome-wide association study between germ line variant genotype and survival outcomes after unrelated-donor BMT. A number of novel genes were found to significantly affect survival outcomes.