A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Three-prime untranslated regions (3′UTRs) of metazoan messenger RNAs (mRNAs) contain numerous regulatory elements, yet remain largely uncharacterized. Using polyA capture, 3′ rapid amplification of complementary DNA (cDNA) ends, full-length cDNAs, and RNA-seq, we defined ∼26,000 distinct 3′UTRs in Caenorhabditis elegans for ∼85% of the 18,328 experimentally supported protein-coding genes and revised ∼40% of gene models. Alternative 3′UTR isoforms are frequent, often differentially expressed during development. Average 3′UTR length decreases with animal age. Surprisingly, no polyadenylation signal (PAS) was detected for 13% of polyadenylation sites, predominantly among shorter alternative isoforms. Trans-spliced (versus non–trans-spliced) mRNAs possess longer 3′UTRs and frequently contain no PAS or variant PAS. We identified conserved 3′UTR motifs, isoform-specific predicted microRNA target sites, and polyadenylation of most histone genes. Our data reveal a rich complexity of 3′UTRs, both genome-wide and throughout development.

Endogenous small interfering RNAs (endo-siRNAs) regulate diverse gene expression programs in eukaryotes by either binding and cleaving mRNA targets or mediating heterochromatin formation; however, the mechanisms of endo-siRNA biogenesis, sorting, and target regulation remain poorly understood. Here we report the identification and function of a specific class of germline-generated endo-siRNAs in Caenorhabditis elegans that are 26 nt in length and contain a guanine at the first nucleotide position (i.e., 26G RNAs). 26G RNAs regulate gene expression during spermatogenesis and zygotic development, and their biogenesis requires the ERI-1 exonuclease and the RRF-3 RNA-dependent RNA polymerase (RdRP). Remarkably, we identified two nonoverlapping subclasses of 26G RNAs that sort into specific RNA-induced silencing complexes (RISCs) and differentially regulate distinct mRNA targets. Class I 26G RNAs target genes are expressed during spermatogenesis, whereas class II 26G RNAs are maternally inherited and silence gene expression during zygotic development. These findings implicate a class of endo-siRNAs in the global regulation of transcriptional programs required for fertility and development.endogenous siRNA ͉ germline ͉ RNA interference S mall RNAs bind Argonaute/Piwi proteins in the RNAinduced silencing complex (RISC) and, through base pairing, guide RISC to silence their cognate targets. While the taxonomy of small RNAs remains fluid, they can be defined in part by nucleotide length, 5Ј nucleotide composition, chemical modifications, genetic requirements for biogenesis, mode of silencing, and biological functions. For example, microRNAs are processed from double-stranded hairpin precursors by the RNase III-like enzyme Dicer to the Ϸ22-nt mature form containing a 5Ј-monophosphate nucleotide. The microRNAs associate with Argonaute (Ago) proteins in RISC and mediate translational repression and/or degradation of their target mRNAs (1). In contrast, Piwi-interacting RNAs (piRNAs) are typically longer than microRNAs, possess a uridine in the first nucleotide, and are generated by a Dicer-independent self-amplification pathway. The piRNAs bind to Piwi proteins in RISC and silence transposons (2).Endogenous small interfering RNAs (endo-siRNAs) represent an emerging class of small RNAs described and characterized in Caenorhabditis elegans by Ambros et al. (3). These endo-siRNAs are perfectly antisense to target transcripts and require the C. elegans Dicer, DCR-1, the RNA-dependent RNA polymerase (RdRP) RRF-3, and the exonuclease ERI-1 for expression (4,5). By large-scale pyrosequencing, Ruby et al. determined that other endo-siRNAs target transcripts associated with spermatogenesis and transposons (6). Therefore, C. elegans endo-siRNAs appear to be a diverse class of small RNAs, with distinct biological functions and genetic requirements for biogenesis. The recent discovery of endo-siRNAs derived from transposable elements, natural antisense transcripts, and hairpin RNAs in Drosophila melanogaster and Mus musculus (7-12) fur...

BackgroundCurrent professional society guidelines recommend genetic carrier screening be offered on the basis of ethnicity, or when using expanded carrier screening panels, they recommend to compute residual risk based on ethnicity. We investigated the reliability of self-reported ethnicity in 9138 subjects referred to carrier screening. Self-reported ethnicity gathered from test requisition forms and during post-test genetic counseling, and genetic ancestry predicted by a statistical model, were compared for concordance.ResultsWe identified several discrepancies between the two sources of self-reported ethnicity and genetic ancestry. Only 30.3% of individuals who indicated Mediterranean ancestry during consultation self-reported this on requisition forms. Additionally, the proportion of individuals who reported Southeast Asian but were estimated to have a different genetic ancestry was found to depend on the source of self-report. Finally, individuals who reported Latin American demonstrated a high degree of ancestral admixture. As a result, carrier rates and residual risks provided for patient decision-making are impacted if using self-reported ethnicity.ConclusionOur analysis highlights the unreliability of ethnicity classification based on patient self-reports. We recommend the routine use of pan-ethnic carrier screening panels in reproductive medicine. Furthermore, the use of an ancestry model would allow better estimation of carrier rates and residual risks.Electronic supplementary materialThe online version of this article (10.1186/s12863-017-0570-y) contains supplementary material, which is available to authorized users.

Esophageal adenocarcinoma, currently the seventh leading cause of cancer-related death, has been associated with the presence of Barrett metaplasia. The malignant potential of Barrett metaplasia is evidenced by ultimate progression of this condition to invasive adenocarcinoma. We utilized liquid phase separation of proteins with chromatofocusing in the first dimension and nonporous reverse phase HPLC in the second dimension followed by ESI-TOF mass spectrometry to identify proteins differentially expressed in six Barrett metaplasia samples as compared with six esophageal adenocarcinoma samples; all six Barrett samples were obtained from the identical six patients from whom we obtained the esophageal adenocarcinoma tissue. Approximately 300 protein bands were detected by mass mappings, and 38 differentially expressed proteins were identified by LC-MS/MS. The false positive rates of the peptide identifications were evaluated by reversed database searching. Among the proteins that were identified, Rho GDP dissociation inhibitor 2, ␣-enolase, Lamin A/C, and nucleoside-diphosphate kinase A were demonstrated to be up-regulated in both mRNA and protein expression in esophageal adenocarcinomas relative to Barrett metaplasia. Candidate proteins were examined at the mRNA level using high density oligonucleotide microarrays. The cellular expression patterns were verified in both esophageal adenocarcinomas and in Barrett metaplasia by immunohistochemistry. These differentially expressed proteins may have utility as useful candidate markers of esophageal adenocarcinoma. Molecular & Cellular Proteomics 6:987-999, 2007.Esophageal adenocarcinoma is increasing rapidly in Western countries and is currently the seventh leading cause of cancer-related death (1). Esophageal adenocarcinoma has been associated with the presence of Barrett metaplasia, a condition in which the normal squamous epithelium of the esophagus is replaced by columnar epithelium. The malignant potential of this condition is evidenced by the progression of Barrett metaplasia to low grade dysplasia, high grade dysplasia, and ultimately to invasive adenocarcinoma. The risk of developing adenocarcinoma is 30 -125 times higher in people who have Barrett metaplasia than people who do not. The prognosis of patients with esophageal adenocarcinoma remains poor with overall 5-year survival rates of only 5-15% (1). Unfortunately patients often present with regionally advanced disease (2). Given the poor prognosis associated with esophageal adenocarcinoma, it is imperative to improve our understanding of the tumorigenesis and the factors associated with increased risk. It is possible that therapeutic targets or protein markers can be identified that will ultimately facilitate improved patient survival.Proteomics technologies have been used for the identification of candidate markers for early cancer detection (3). The global analysis of protein expression complements genomics analyses. For example, proteomics analysis may provide further insight into post-translational mod...