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During the peak of hospitalizations of patients with severe Covid-19 in Italy and Spain in March, a group of researchers in these and other countries obtained and analyzed samples, resulting in the identification of two chromosomal loci associated with the disorder.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C , we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation. Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Longevity is a complex phenotype influenced by both environmental and genetic factors. The genetic contribution is estimated at about 25%. Despite extensive research efforts, only a few longevity genes have been validated across populations. Long-lived individuals (LLI) reach extreme ages with a relative low prevalence of chronic disability and major age-related diseases (ARDs). We tested whether the protection from ARDs in LLI can partly be attributed to genetic factors by calculating polygenic risk scores (PRSs) for seven common late-life diseases (Alzheimer’s disease (AD), atrial fibrillation (AF), coronary artery disease (CAD), colorectal cancer (CRC), ischemic stroke (ISS), Parkinson’s disease (PD) and type 2 diabetes (T2D)). The examined sample comprised 1351 German LLI (≥94 years, including 643 centenarians) and 4680 German younger controls. For all ARD-PRSs tested, the LLI had significantly lower scores than the younger control individuals (areas under the curve (AUCs): ISS = 0.59, p = 2.84 × 10−35; AD = 0.59, p = 3.16 × 10−25; AF = 0.57, p = 1.07 × 10−16; CAD = 0.56, p = 1.88 × 10−12; CRC = 0.52, p = 5.85 × 10−3; PD = 0.52, p = 1.91 × 10−3; T2D = 0.51, p = 2.61 × 10−3). We combined the individual ARD-PRSs into a meta-PRS (AUC = 0.64, p = 6.45 × 10−15). We also generated two genome-wide polygenic scores for longevity, one with and one without the TOMM40/APOE/APOC1 gene region (AUC (incl. TOMM40/APOE/APOC1) = 0.56, p = 1.45 × 10−5, seven variants; AUC (excl. TOMM40/APOE/APOC1) = 0.55, p = 9.85 × 10−3, 10,361 variants). Furthermore, the inclusion of nine markers from the excluded region (not in LD with each other) plus the APOE haplotype into the model raised the AUC from 0.55 to 0.61. Thus, our results highlight the importance of TOMM40/APOE/APOC1 as a longevity hub.

Abstract Hybridisation-based targeted enrichment is a widely used and well-established technique in high-throughput second-generation short-read sequencing. Despite the high potential to genetically resolve highly repetitive and variable genomic sequences by, for example PacBio third-generation sequencing, targeted enrichment for long fragments has not yet established the same high-throughput due to currently existing complex workflows and technological dependencies. We here describe a scalable targeted enrichment protocol for fragment sizes of >7 kb. For demonstration purposes we developed a custom blood group panel of challenging loci. Test results achieved > 65% on-target rate, good coverage (142.7×) and sufficient coverage evenness for both non-paralogous and paralogous targets, and sufficient non-duplicate read counts (83.5%) per sample for a highly multiplexed enrichment pool of 16 samples. We genotyped the blood groups of nine patients employing highly accurate phased assemblies at an allelic resolution that match reference blood group allele calls determined by SNP array and NGS genotyping. Seven Genome-in-a-Bottle reference samples achieved high recall (96%) and precision (99%) rates. Mendelian error rates were 0.04% and 0.13% for the included Ashkenazim and Han Chinese trios, respectively. In summary, we provide a protocol and first example for accurate targeted long-read sequencing that can be used in a high-throughput fashion. Graphical Abstract Graphical Abstract We developed a high-throughput hybridisation-based targeted enrichment protocol for third-generation sequencing application. Long fragments of >7 kb can be efficiently enriched in 16× sample multiplexing resulting in >6 kb HiFi reads.

Background Mucocutaneous blistering is characteristic of autoimmune bullous dermatoses (AIBD). Blisters are caused by autoantibodies directed against structural components of the skin. Hence, detection of specific autoantibodies has become a hallmark for AIBD diagnosis. Studies on prevalence of AIBD autoantibodies in healthy individuals yielded contradictory results. Methods To clarify this, samples from 7063 blood donors were tested for presence of anti-BP180-NC16A, anti-BP230 and anti-Dsg1/3 IgG by indirect immunofluorescence (IF) microscopy using a biochip. Results Cumulative prevalence of these autoantibodies was 0.9 % (CI: 0.7–1.1 %), with anti-BP180-NC16A IgG being most prevalent. Validation of IF findings using ELISA confirmed presence of autoantibodies in 7/15 (anti-Dsg1), 6/7 (anti-Dsg3), 35/37 (anti-BP180-NC16A) and 2/3 (anti-BP230) cases. Moreover, in 16 samples, anti-BP180-NC16A autoantibody concentrations exceeded the cut-off for the diagnosis of bullous pemphigoid. Interestingly, these anti-BP180-NC16A autoantibodies from healthy individuals formed immune complexes with recombinant antigen and dose-dependently activated neutrophils in vitro . However, fine-epitope mapping within NC16A showed a different binding pattern of anti-BP180-NC16A autoantibodies from healthy individuals compared to bullous pemphigoid patients, while IgG subclasses were identical. Conclusions Collectively, we here report a low prevalence of AIBD autoantibodies in a large cohort of healthy individuals. Furthermore, functional analysis shows differences between autoantibodies from healthy donors and AIBD patients.

Background/Objectives: In this ongoing, multicenter, global cohort observational study, phenotypes of headaches after COVID-19 vaccination were directly compared between different vaccines. Methods: Phenotypes of postvaccinal headache were recorded in 18,544 participants. The study was launched immediately after the start of the global COVID-19 vaccination campaign on 12 January 2021 and continued until 1 August 2023. Specific aspects of headaches and related variables were collected via an online questionnaire. The clinical headache characteristics of patients vaccinated with the Comirnaty (BioNTech), Jcovden (Johnson & Johnson), Sputnik V (Gamelaya), Covilo (Sinopharm), Spikevax (Moderna), Vaxzevria (AstraZeneca), and Convidecia (CanSino Biologics) vaccines were investigated. Results: Across all vaccines, the median and mean latency of headache onset after vaccine administration were 12 h and 23.3 h, respectively. The median and mean headache duration were 12 h and 23.3 h, respectively. When the nonreplicating viral vector vaccine Sputnik V was used, headaches occurred the fastest, with a latency of 17 h. The latencies for the Vaxzevria and Convidecia nonreplicating viral vector vaccines were 14.9 h and 19.1 h, respectively. The Covilo inactivated whole-virus vaccine had a latency of 20.5 h. The latencies of the mRNA-based Comirnaty and Spikevax vaccines were 26.0 h and 22.02 h, respectively. Analysis of variance revealed no significant differences in the mean duration of postvaccinal headache for the vaccines tested. Compared with the Comirnaty, Covilo, and Vaxzevria vaccines, the Spikevax vaccine induced significantly greater headache intensities. Vaxzevria was associated with a significantly higher frequency of concomitant symptoms than the other vaccines. Conclusions: The phenotype of postvaccinal headache can vary significantly between vaccines. These results have clinical implications for differentiating between postvaccinal headache and other primary and secondary headaches. This knowledge is clinically relevant in differentiating life-threatening vaccination complications, such as thrombotic syndromes, which are also associated with headaches. Based on these results, new diagnostic criteria for postvaccinal headaches can be developed.

Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms.

Although many potential causes have been established for recurrent implantation failure (RIF) and recurrent miscarriage (RM), about 50% of these remain idiopathic. Scientific research is focused on immunological risk factors. In the present study, we aim to evaluate live birth rates after immunization with paternal lymphocytes (lymphocyte immunotherapy (LIT)). This retrospective study consisted of 148 couples with a history of RM and/or RIF. The women underwent immunization with lymphocytes of their respective partners from November 2017 to August 2019. Fifty-five patients (43%) had live births. Stratified by indication (RM, RIF, combined), live birth rates in the RM and the combined group were significantly higher than that in the RIF group (53%, 59% and 33%, respectively, p = 0.02). The difference was especially noticeable during the first 90 days after immunization (conception rate leading to live births: 31%, 23% and 8% for RM, the combined group and RIF, respectively; p = 0.005), while there was no difference between groups during the later follow-up. LIT was associated with high live birth rates, especially in women with recurrent miscarriage. In view of the limited data from randomized studies, LIT cannot be recommended as routine therapy. However, it may be considered in individual cases.

Background: Due to findings on adverse reactions and clinical efficacy of different vaccinations against SARS-CoV-2, the administration of vaccination regimens containing both adenoviral vector vaccines and mRNA-based vaccines has become common. Data are still needed on the direct comparison of immunogenicity for these different regimens. Methods: We compared markers for immunogenicity (anti-S1 IgG/IgA, neutralizing antibodies, and T-cell response) with three different vaccination regimens (homologous ChAdOx1 nCoV-19 (n = 103), or mixture of ChAdOx1 nCoV-19 with mRNA-1273 (n = 116) or BNT162b2 (n = 105)) at two time points: the day of the second vaccination as a baseline and 14 days later. Results: All examined vaccination regimens elicited measurable immune responses that were significantly enhanced after the second dose. Homologous ChAdOx1 nCoV-19 was markedly inferior in immunogenicity to all other examined regimens after administration of the second dose. Between the heterologous regimens, mRNA-1273 as second dose induced greater antibody responses than BNT162b2, with no difference found for neutralizing antibodies and T-cell response. Discussion: While these findings allow no prediction about clinical protection, from an immunological point of view, vaccination against SARS-CoV-2 with an mRNA-based vaccine at one or both time points appears preferable to homologous vaccination with ChAdOx1 nCoV-19. Whether or not the demonstrated differences between the heterologous regimens are of clinical significance will be subject to further research.

SARS-CoV-2 serosurveillance is important to adapt infection control measures and estimate the degree of underreporting. Blood donor samples can be used as a proxy for the healthy adult population. In a repeated cross-sectional study from April 2020 to April 2021, September 2021, and April/May 2022, 13 blood establishments collected 134,510 anonymised specimens from blood donors in 28 study regions across Germany. These were tested for antibodies against the SARS-CoV-2 spike protein and nucleocapsid, including neutralising capacity. Seroprevalence was adjusted for test performance and sampling and weighted for demographic differences between the sample and the general population. Seroprevalence estimates were compared to notified COVID-19 cases. The overall adjusted SARS-CoV-2 seroprevalence remained below 2% until December 2020 and increased to 18.1% in April 2021, 89.4% in September 2021, and to 100% in April/May 2022. Neutralising capacity was found in 74% of all positive specimens until April 2021 and in 98% in April/May 2022. Our serosurveillance allowed for repeated estimations of underreporting from the early stage of the pandemic onwards. Underreporting ranged between factors 5.1 and 1.1 in the first two waves of the pandemic and remained well below 2 afterwards, indicating an adequate test strategy and notification system in Germany.