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Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Circular RNAs (circRNAs), an important class of regulatory RNAs, have been shown to be the most prevalent in the brain compared with other tissues. However the processes governing their biogenesis in neurons are still elusive. Moreover, little is known about whether and how different biogenesis factors work in synchrony to generate neuronal circRNAs. To address this question, we pharmacologically inhibited the spliceosome and profiled rat neuronal circRNAs using RNA sequencing. We identified over 100 circRNAs that were up-regulated and a few circRNAs that were down-regulated upon spliceosome inhibition. Bioinformatic analysis revealed that up-regulated circRNAs possess significantly longer flanking introns compared with the un-changed circRNA population. Moreover, the flanking introns of up-regulated circRNAs harbor a higher number of distinct repeat sequences and more reverse complementary motifs compared with the unchanged circRNAs. Taken together, our data demonstrate that the biogenesis of circRNAs containing distinct intronic features becomes favored under conditions of limited spliceosome activity.