SummaryBackgroundRestless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets.MethodsIn the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.FindingsWe identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).InterpretationIdentification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.FundingDeutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Since the development of the first assay in 1989 (20), assays for detection of hepatitis C virus (HCV) antibodies (Ab) have allowed progress in the early detection of HCV infection (46). This increased sensitivity of the last-generation assays has dramatically reduced the risk of HCV transmission by blood components by reducing the window period from 82 days (5) to 66 days (3, 12). To further reduce the residual risk (2,5,16,18,36,37,41,48), nucleic acid testing (NAT) for HCV RNA was introduced in several high-income countries (2,14,15,21,30,39). In some countries, an assay for the detection of HCV core antigen (Ag) by use of the enzyme immunoassay (EIA) technology has been chosen as an alternative to NAT for the early diagnosis of infection (1,8,25,38). In addition, some authors emphasized the clinical advantage of HCV core Ag quantification as a direct marker of viral replication in the chronic phase of infection (4) and as a relevant marker for predicting and monitoring the response to therapy (7,29,31). Indeed, the HCV core Ag assays have sensitivities close to that of NAT, with mean detection differences of 1 to 2 days in the window period with the specific assay developed for blood screening (11,32,35,45) and 0.29 day with the immunoassay capable of detecting and quantifying HCV core Ag (23). A recent study reported that a prototype assay based on the simultaneous detection of HCV core Ag and anti-HCV Ab significantly closed the time gap between HCV RNA detection and the first appearance of detectable anti-HCV Ab (42). However, this assay is not yet available for routine use. More recently, a new combination assay has been developed and licensed in Europe (Monolisa HCV Ag/Ab ULTRA; Bio-Rad, Marnes la Coquette, France). To assess its sensitivity for the detection of HCV infection during the window period or at the early phase after seroconversion, we tested two panels and compared the results with those obtained using the two available assays for HCV Ag (HCV core Ag EIA blood screening assay and trak-C assay) and HCV RNA. The overall objective was to determine if this new test could constitute an alternative to NAT for the diagnosis of HCV infection during the window period and whether the sensitivity for antibody detection is preserved. (Table 1) consisted of 12 blood donor samples which were negative for anti-HCV Ab (Ortho HCV 3.0 EIA test system Enhanced SAVe; Ortho Clinical Diagnostics, Raritan, NJ) but positive for HCV RNA. The plasma from each of these blood donations was immediately aliquoted and stored at Ϫ30°C until it was MATERIALS AND METHODS Panels

This new developed assay presents an improvement for the detection of HCV infection, especially in the early phase of infection when antibodies are undetectable. Although less sensitive than NAT, this assay could be a suitable solution for blood screening in developing countries where NAT (or HCV core antigen-specific assay) is not affordable or its implementation is not feasible.

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.