An analysis of genetically regulated gene expression across multiple tissues implicates novel gene candidates in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) have successfully identified multiple independent genetic loci that harbour variants associated with Alzheimer's disease, but the exact causal genes and biological pathways are largely unknown. METHODS: To prioritise likely causal genes associated with Alzheimer's disease, we used S-PrediXcan to integrate expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression (GTEx) study and CommonMind Consortium (CMC) with Alzheimer's disease GWAS summary statistics. We meta-analysed the GTEx results using S-MultiXcan, prioritised disease-implicated loci using a computational fine-mapping approach, and performed a biological pathway analysis on the gene-based results. RESULTS: We identified 126 tissue-specific gene-based associations across 48 GTEx tissues, targeting 50 unique genes. Meta-analysis of the tissue-specific associations identified 73 genes whose expression was associated with Alzheimer's disease. Additional analyses in the dorsolateral prefrontal cortex from the CMC identified 12 significant associations, 8 of which also had a significant association in GTEx tissues. Fine-mapping of causal gene sets prioritised gene candidates in 10 Alzheimer's disease loci with strong evidence for causality. Biological pathway analyses of the meta-analysed GTEx data and CMC data identified a significant enrichment of Alzheimer's disease association signals in plasma lipoprotein clearance, in addition to multiple immune-related pathways. CONCLUSIONS: Gene expression data from brain and peripheral tissues can improve power to detect regulatory variation underlying Alzheimer's disease. However, the associations in peripheral tissues may reflect tissue-shared regulatory variation for a gene. Therefore, future functional studies should be performed to validate the biological meaning of these associations and whether they represent new pathogenic tissues.

End-Stage Kidney Disease following Surgical Management of Kidney Cancer.

BACKGROUND AND OBJECTIVES: We investigated the incidence of ESKD after surgical management of kidney cancer in the Australian state of Queensland, and described patterns in the initiation of kidney replacement therapy resulting from kidney cancer across Australia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All newly diagnosed cases of kidney cancer in the Australian state of Queensland between January of 2009 and December of 2014 were ascertained through the Queensland Cancer Registry. There were 2739 patients included in our analysis. Patients who developed ESKD were identified using international classification of disease-10-coded hospital administrative data. Incidence rate and 3-year cumulative incidence were calculated, and multivariable Cox proportional hazards models were used to identify factors associated with ESKD. Additional descriptive analysis was undertaken of Australian population data. RESULTS: The incidence rate of ESKD in all patients was 4.9 (95% confidence interval [95% CI], 3.9 to 6.2) per 1000 patient-years. The 3-year cumulative incidence was 1.7%, 1.9%, and 1.0% for all patients, and patients managed with radical or partial nephrectomy, respectively. Apart from preoperative kidney disease, exposures associated with increased ESKD risk were age≥65 years (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.2 to 3.2), male sex (aHR, 2.3; 95% CI, 1.3 to 4.3), preoperative diabetes (aHR, 1.8; 95% CI, 1.0 to 3.3), American Society of Anesthesiologists classification ≥3 (aHR, 4.0; 95% CI, 2.2 to 7.4), socioeconomic disadvantage (aHR, 1.6; 95% CI, 0.9 to 2.7), and postoperative length of hospitalization ≥6 days (aHR, 2.1; 95% CI, 1.4 to 3.0). Australia-wide trends indicate that the rate of kidney replacement therapy after oncologic nephrectomy doubled between 1995 and 2015, from 0.3 to 0.6 per 100,000 per year. CONCLUSIONS: In Queensland between 2009 and 2014, one in 53 patients managed with radical nephrectomy and one in 100 patients managed with partial nephrectomy developed ESKD within 3 years of surgery. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_28_CJASNPodcast_18_1_.mp3.