Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses.

The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire's central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Pharmacist Care to Improve Medication Adherence and Quality Of Life of COPD Patients

The objective of this study was to determine whether pharmaceutical care by pharmacists could improve medication adherence and quality of life in patients with chronic obstructive pulmonary disease or not. A prospective interventional study was conducted among 156 patients to assess medication adherence and find the reason for non-adherence, analyze the quality of life, and provide counseling to improve the quality of life in patients, to determine whether pharmaceutical care by pharmacists could improve medication adherence as well as the quality of life and to prepare patient information leaflet to educate the patients regarding the disease. Prescriptions were collected and Medication Adherence Questionnaire and St. George’s Respiratory Questionnaire were used to assess medication adherence and quality of life respectively. Among 156 patients, 76 were taken as a control group and the other 80 were taken as an intervention group. At the baseline, the patients in both intervention and control groups were found to have no significant difference. After the second follow-up, the total quality of life score was improved significantly in the intervention group when compared with the control group (53.55 ± 6.79 vs.68.89 ± 9.13, p=0.001).&nbsp; Medication adherence was significantly improved after pharmacist intervention (6.38 ± 1.53, 7.42 ± 0.74, p=0.001)&nbsp; as compared with control group(4.73 ± 2.16, 4.89 ± 2.18, p=0.01). As per the study results, the implementation of pharmacist intervention played an important role in improving medication adherence as well as the quality of life of chronic obstructive pulmonary disease patients. It may improve patient outcomes and reduce their social and economic burdens. Keywords: Pharmacist intervention, Medication adherence, COPD, MAQ, SGRQ

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg &gt; 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Genome-wide association study of musical beat synchronization demonstrates high polygenicity

Moving in synchrony to the beat is a fundamental component of musicality. Here we conducted a genome-wide association study to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with 69 loci reaching genome-wide significance (P < 5 × 10−8) and single-nucleotide-polymorphism-based heritability (on the liability scale) of 13%–16%. Heritability was enriched for genes expressed in brain tissues and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central-nervous-system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through separate experiments) and of the genome-wide association study (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations

Genome-wide association study of musical beat synchronization demonstrates high polygenicity

Moving in synchrony to the beat is a fundamental component of musicality. Here we conducted a genome-wide associa- tion study to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat syn- chronization exhibited a highly polygenic architecture, with 69 loci reaching genome-wide significance (P < 5 × 10−8) and single-nucleotide-polymorphism-based heritability (on the liability scale) of 13%–16%. Heritability was enriched for genes expressed in brain tissues and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central-nervous-system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through separate experiments) and of the genome-wide association study (polygenic scores for beat synchroniza- tion were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations

Genetic Consequences of the Transatlantic Slave Trade in the Americas

According to historical records of transatlantic slavery, traders forcibly deported an estimated 12.5 million people from ports along the Atlantic coastline of Africa between the 16th and 19th centuries, with global impacts reaching to the present day, more than a century and a half after slavery’s abolition. Such records have fueled a broad understanding of the forced migration from Africa to the Americas yet remain underexplored in concert with genetic data. Here, we analyzed genotype array data from 50,281 research participants, which—combined with historical shipping documents—illustrate that the current genetic landscape of the Americas is largely concordant with expectations derived from documentation of slave voyages. For instance, genetic connections between people in slave trading regions of Africa and disembarkation regions of the Americas generally mirror the proportion of individuals forcibly moved between those regions. While some discordances can be explained by additional records of deportations within the Americas, other discordances yield insights into variable survival rates and timing of arrival of enslaved people from specific regions of Africa. Furthermore, the greater contribution of African women to the gene pool compared to African men varies across the Americas, consistent with literature documenting regional differences in slavery practices. This investigation of the transatlantic slave trade, which is broad in scope in terms of both datasets and analyses, establishes genetic links between individuals in the Americas and populations across Atlantic Africa, yielding a more comprehensive understanding of the African roots of peoples of the Americas

Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659). We observed consistent positive genetic correlations with substance use and obesity in both cohorts. Other genetic correlations were discrepant, including positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in the UKB, and genetic correlations with cognition that were negative in 23andMe but positive in the UKB. Phenome-wide association study using polygenic scores of coffee intake derived from 23andMe or UKB summary statistics also revealed consistent associations with increased odds of obesity- and red blood cell-related traits, but all other associations were cohort-specific. Our study shows that the genetics of coffee intake associate with substance use and obesity across cohorts, but also that GWAS performed in different populations could capture cultural differences in the relationship between behavior and genetics.</p