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There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson’s disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson’s disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson’s disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson’s disease (28 568 cases) were obtained from the International Parkinson’s Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10−8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson’s disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = −2.364, 95% confidence interval (CI) = −4.789–0.060; years difference per 1 log-unit increase = −2.011, 95% CI = −3.706 to −0.317; years difference per 1 log-unit increase = −1.569, 95% CI = −2.891 to −0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson’s disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson’s disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson’s disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson’s disease.

Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental effects. To identify molecular targets for treatment, genome-wide association study meta-analyses (GWAMAs) of CKD-defining traits have identified hundreds of genetic loci in aggregated populations. However, while GWAMAs estimate the average allelic effect across studies, single population studies may be relevant to unravel specific mechanisms. To assess whether an individual study from a specific population could extend existing knowledge on kidney function genetics, we selected 147 kidney function relevant loci identified by a large European ancestry GWAMA, assessing their association with the glomerular filtration rate estimated from serum creatinine (eGFRcrea) in the Cooperative Health Research In South Tyrol (CHRIS) study (n=10,146), conducted in an Alpine region where thyroid dysfunction is common. We replicated associations with single nucleotide polymorphisms (SNPs) at 11 loci, showing up-to-5.4 times larger effect sizes than in the corresponding GWAMA, not explainable by minor allele frequency differences. Systematic mediation analysis across 70 quantitative traits identified serum magnesium, the activated partial thromboplastin time, and serum urate as partial mediators of the eGFRcrea associations atSHROOM3,SLC34A1, andIGF1R, respectively. Given that free triiodothyronine and thyroxine were effect modifiers across all loci, we conducted SNP-by-thyroid stimulating hormone (TSH) interaction analyses, identifying significant interactions atSTC1: SNPs had larger effects on eGFRcrea at higher TSH levels, possibly reflecting stanniocalcin-1 autocrine and paracrine role. Individual population studies can help characterize genetic associations. The interplay between phenotypes atSHROOM3andSLC34A1and the role of thyroid function as a genetic effect modifier warrant further investigations.

To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandemic intensity and public health interventions, COVID-19-related symptoms (odds ratio, OR:8.26; 95% confidence interval, CI:6.04–11.31), contacts with infected individuals within home (OR:7.47, 95%CI:3.81–14.62) or outside home (OR:9.87, 95%CI:5.78–16.85), and being retired (OR:0.50, 95%CI:0.34-0.73). Symptoms and next within- and outside-home contacts were the leading determinants of swab testing predisposition in the most acute phase of the pandemics. Testing was not associated with age, sex, education, comorbidities, or lifestyle factors. In the study area, contextual determinants reflecting the course of the pandemic were predominant compared to individual sociodemographic characteristics in explaining the SARS-CoV-2 probability of testing. Decision makers should evaluate whether the intended target groups were correctly prioritized by the testing campaign.

The COVID-19 pandemic has been threatening the healthcare and socioeconomic systems of entire nations. While population-based surveys to assess the distribution of SARS-CoV-2 infection have become a priority, pre-existing longitudinal studies are ideally suited to assess the determinants of COVID-19 onset and severity.The Cooperative Health Research In South Tyrol (CHRIS) study completed the baseline recruitment of 13,393 adults from the Venosta/Vinschgau rural district in 2018, collecting extensive phenotypic and biomarker data, metabolomic data, densely imputed genotype and whole-exome sequencing data.Based on CHRIS, we designed a prospective study, called CHRIS COVID-19, aimed at: 1) estimating the incidence of SARS-CoV-2 infections; 2) screening for and investigating the determinants of incident infection among CHRIS participants and their household members; 3) monitoring the immune response of infected participants prospectively.An online screening questionnaire was sent to all CHRIS participants and their household members. A random sample of 1450 participants representative of the district population was invited to assess active (nasopharyngeal swab) or past (serum antibody test) infections. We prospectively invited for complete SARS-CoV-2 testing all questionnaire completers gauged as possible cases of past infection and their household members. In positive tested individuals, antibody response is monitored quarterly for one year. Untested and negative participants receive the screening questionnaire every four weeks until gauged as possible incident cases or till the study end.Originated from a collaboration between researchers and community stakeholders, the CHRIS COVID-19 study aims at generating knowledge about the epidemiological, molecular, and genetic characterization of COVID-19 and its long-term sequelae.

Background: Body mass index (BMI) and waist-hip-ratio (WHR) are measures of adiposity, the former being a good marker for overall total body fat, the latter describing regional adiposity. Higher adiposity has been associated with the increased prevalence of many chronic diseases and a positive association between BMI and increased hospital admissions has previously been established. The aim of this study was to estimate the causal relationship between BMI, WHR and WHR adjusted for BMI (WHRadjBMI) and yearly hospital admission rates. Methods and Findings Mendelian randomization (MR) approaches were used to test the causal effect of BMI, WHR and WHRadjBMI on yearly hospital admission rates. Using data on 310,471 participants of White-British ancestry from the UK Biobank, we performed one-sample and two-sample MR analyses on the exposures individually and in a multivariable setting. MR analyses supported a causal role of adiposity on hospital admissions, with consistency across one- and two-sample MR methods. Primarily, one-sample MR analyses estimated fold-increases in yearly hospital admission rates of 1.13 (95% CI: 1.02, 1.27), 1.26 (95% CI: 1.00, 1.58) and 1.22 (95% CI: 1.01, 1.47) per SD for BMI, WHR and WHRadjBMI, respectively. A multivariable approach yielded estimates of 1.04 (95% CI: 0.99, 1.03) for BMI and 1.31 (95% CI: 1.04, 1.67) for WHR, while adjusting for WHR and BMI, respectively. Conclusions The results support a causal role of higher BMI and WHR in increasing the yearly hospital admission rate. The attenuation of the BMI effect, when adjusting for WHR in the multivariable MR analyses, suggested that an adverse fat distribution, rather than a higher BMI itself, may drive the relationship between adiposity and increased risk of hospital admission. Keywords: Body mass index (BMI), waist-hip-ratio (WHR), hospital admission, Mendelian randomization

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease associated with sudden cardiac death and cardiac fibro-fatty replacement. Over the last years, several works have demonstrated that different epigenetic enzymes can affect not only gene expression changes in cardiac diseases but also cellular metabolism. Specifically, the histone acetyltransferase GCN5 is known to facilitate adipogenesis and modulate cardiac metabolism in heart failure. Our group previously demonstrated that human primary cardiac stromal cells (CStCs) contribute to adipogenesis in the ACM pathology. Thus, this study aims to evaluate the role of GCN5 in ACM intracellular lipid accumulation. To do so, CStCs were obtained from right ventricle biopsies of ACM patients and from samples of healthy cadaveric donors (CTR). GCN5 expression was increased both in ex vivo and in vitro ACM samples compared to CTR. When GCN5 expression was silenced or pharmacologically inhibited by the administration of MB-3, we observed a reduction in lipid accumulation and a mitigation of reactive oxygen species (ROS) production in ACM CStCs. In agreement, transcriptome analysis revealed that the presence of MB-3modified the expression of pathways related to cellular redox balance. Altogether, our findings suggest that GCN5 inhibition reduces fat accumulation in ACM CStCs, partially by modulating intracellular redox balance pathways.

Complement genes encompass a wide array of variants, giving rise to numerous protein isoforms that have often been shown to exhibit clinical significance. Given that these variants have been discovered over a span of 50 y, one challenging consequence is the inconsistency in the terminology used to classify them. This issue is prominently evident in the nomenclature used for complement C6 and C7 variants, for which we observed a great discrepancy between previously published works and variants described in current genome browsers. This report discusses the causes for the discrepancies in C6 and C7 nomenclature and seeks to establish a classification system that would unify existing and future variants. The inconsistency in the methods used to annotate amino acids and the modifications pinpointed in the C6 and C7 primers are some of the factors that contribute greatly to the discrepancy in the nomenclature. Several variants that were classified incorrectly are highlighted in this report, and we showcase first-hand how a unified classification system is important to match previous with current genetic information. Ultimately, we hope that the proposed classification system of nomenclature becomes an incentive for studies on complement variants and their physiological and/or pathological effects.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Uncontrolled hypertension is caused by various factors including compliance issues, patient specific drug uptake and elimination profiles or secondary forms of hypertension, resulting in blood pressure control rates of less that 50%. RAAS Triple-A profiling is a high-throughput mass-spectrometry based assay for Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone in serum samples. Hormone levels are used to calculate markers for plasma-renin-activity (PRA-S), plasma angiotensin-converting-enzyme activity (ACE-S) and adrenal aldosterone secretion (AA2-Ratio). The integrated analysis of these molecular markers together with drug prescription information allows to identify the underlying cause of uncontrolled hypertension, including primary aldosteronism and insufficiency in drug adherence or dosing for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs). 500 participants with prescribed antihypertensive drugs were selected from the “Cooperative Health Research in South Tyrol” (CHRIS) study, a population-based study from an Alpine rural environment. Five age- and sex-matched groups (N=100 each) selected were individuals on single therapy with ARBs, ACEi or beta blockers, and on single pill dual therapy of ACEi or ARBs in combination with diuretics. Three age and sex-matched control groups of 100 participants each were included, being normotensive, hypertensive (treated with non-antihypertensive drugs) and hypertensive participants without any prescribed medication. RAAS Triple-A analysis was performed in all individuals and reference values for Ang I, Ang II, Aldosterone, PRA-S, ACE-S and AA2-Ratio were established in appropriate sub-populations. Drug monitoring by LC-MS/MS based quantification of anti-hypertensive drugs in serum was used as a gold standard to determine cut-off values for compliance with ARB and ACEi therapy and ROC analysis was performed using angiotensin-based biomarkers.

Background and aims Cardiovascular disease (CVD) is the leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD), both with and without type 2 diabetes mellitus (T2DM). Cardiac autonomic dysfunction is a risk factor for CVD morbidity and mortality. The aim of this pilot study was to assess whether there is an association between NAFLD and impaired cardiac autonomic function. Methods and results Among the first 4979 participants from the Cooperative Health Research in South Tyrol (CHRIS) study, we randomly recruited 173 individuals with T2DM and 183 age- and sex-matched nondiabetic controls. Participants underwent ultrasonography and vibration-controlled transient elastography (Fibroscan®, Echosens) to assess hepatic steatosis and liver stiffness. The low-to-high-frequency (LF/HF) power ratio and other heart rate variability (HRV) measures were calculated from a 20-min resting electrocardiogram (ECG) to derive a measure of cardiac sympathetic/parasympathetic imbalance. Among the 356 individuals recruited for the study, 117 had NAFLD and T2DM, 56 had T2DM alone, 68 had NAFLD alone, and 115 subjects had neither condition. Individuals with T2DM and NAFLD (adjusted odds ratio [OR] 4.29, 95% confidence intervals [CI] 1.90–10.6) and individuals with NAFLD alone (adjusted OR 3.41, 95% CI 1.59–7.29), but not those with T2DM alone, had a substantially increased risk of having cardiac sympathetic/parasympathetic imbalance, compared with those without NAFLD and T2DM. Logistic regression models were adjusted for age, sex, body mass index (BMI), hypertension, dyslipidemia, insulin resistance, hemoglobin A1c (HbA1c), C-reactive protein (CRP), and Fibroscan®-measured liver stiffness. Conclusions NAFLD was associated with cardiac sympathetic/parasympathetic imbalance, regardless of the presence or absence of T2DM, liver stiffness, and other potential confounding factors.

BackgroundCommunity-based studies are essential to quantify the spread of SARS-CoV-2 infection and for unbiased characterization of its determinants and outcomes. We conducted a cross-sectional study in the Gardena valley, a major Alpine touristic destination which was struck in the expansion phase of the COVID-19 pandemic over the winter 2020.MethodsWe surveyed 2244 representative study participants who underwent swab and serum antibody tests. We made multiple comparisons among the Abbott and Diasorin bioassays and serum neutralization titers. Seroprevalence accounted for the stratified design, non-response and test accuracy. Determinants and symptoms predictive of infection were analyzed by weighted multiple logistic regression.ResultsSARS-CoV-2 seroprevalence was 26.9% (95% confidence interval: 25.2%, 28.6%) by June 2020. The serum antibody bioassays had modest agreement with each other. Receiver operating characteristic curve analysis on the serum neutralizing capacity showed better performance of the Abbott test at lower than the canonical threshold. Socio-demographic characteristics showed no clear evidence of association with seropositivity, which was instead associated with place of residence and economic activity. Loss of taste or smell, fever, difficulty in breathing, pain in the limbs, and weakness were the most predictive symptoms of positive antibody test results. Fever and weakness associations were age-dependent.ConclusionThe Gardena valley had one of the highest SARS-CoV-2 infection prevalence in Europe. The age-dependent risk associated with COVID-19 related symptoms implies targeted strategies for screening and prophylaxis planning.

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value &lt, 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.

Estimating the spread of SARS-CoV-2 infection in communities is critical. We surveyed 2244 stratified random sample community members of the Gardena valley, a winter touristic area, amidst the first expansion phase of the COVID-19 pandemic in Europe. We measured agreement between Diasorin and Abbott serum bioassay outputs and the Abbott optimal discriminant threshold of serum neutralisation titres with recursive receiver operating characteristic curve. We analytically adjusted serum antibody tests for unbiased seroprevalence estimate and analysed the determinants of infection with non-response weighted multiple logistic regression. SARS-CoV-2 seroprevalence was 26.9% (95% CI 25.2–28.6) by June 2020. The bioassays had a modest agreement with each other. At a lower threshold than the manufacturer's recommended level, the Abbott assay reflected greater discrimination of serum neutralisation capacity. Seropositivity was associated with place and economic activity, not with sex or age. Symptoms like fever and weakness were age-dependent. SARS-CoV-2 mitigation strategies should account for context in high prevalence areas.

The identification of genetic variants that predispose individuals to cardiovascular disease and a better understanding of their targets would be highly advantageous. Genome-wide association studies have identified variants that associate with QT-interval length (a measure of myocardial repolarization). Three of the strongest associating variants (single-nucleotide polymorphisms) are located in the putative promotor region of CNOT1, a gene encoding the central CNOT1 subunit of CCR4-NOT: a multifunctional, conserved complex regulating gene expression and mRNA stability and turnover. We isolated the minimum fragment of the CNOT1 promoter containing all three variants from individuals homozygous for the QT risk alleles and demonstrated that the haplotype associating with longer QT interval caused reduced reporter expression in a cardiac cell line, suggesting that reduced CNOT1 expression might contribute to abnormal QT intervals. Systematic siRNA-mediated knockdown of CCR4-NOT components in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) revealed that silencing CNOT1 and other CCR4-NOT genes reduced their proliferative capacity. Silencing CNOT7 also shortened action potential duration. Furthermore, the cardiac-specific knockdown of Drosophila orthologs of CCR4-NOT genes in vivo (CNOT1/Not1 and CNOT7/8/Pop2) was either lethal or resulted in dilated cardiomyopathy, reduced contractility or a propensity for arrhythmia. Silencing CNOT2/Not2, CNOT4/Not4 and CNOT6/6L/twin also affected cardiac chamber size and contractility. Developmental studies suggested that CNOT1/Not1 and CNOT7/8/Pop2 are required during cardiac remodeling from larval to adult stages. To summarize, we have demonstrated how disease-associated genes identified by GWAS can be investigated by combining human cardiomyocyte cell-based and whole-organism in vivo heart models. Our results also suggest a potential link of CNOT1 and CNOT7/8 to QT alterations and further establish a crucial role of the CCR4-NOT complex in heart development and function. This article has an associated First Person interview with the first author of the paper., Summary: Genome-wide association studies combined with in vitro human cardiac cell assays and a model organism suitable for heart studies in vivo connect CNOT1, CNOT7 and overall the CCR4-NOT complex to human heart disease and morbidity.

Despite the proven superiority of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) over the Cockcroft&ndash, Gault (CG) formula, current guidelines recommend the latter to assess renal function in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). To assess the relationship between the CG and the recommended CKD-EPI formulas, in a cohort of atrial fibrillation (AF) patients treated with NOACs, and the misclassifications introduced by the CG formula for renal function levels, we estimated renal function with three equations: CG, CKD-EPI with body surface adjustment (1.73 mL/m2, CKD-EPI) and without such adjustment (CKD-EPI_noBSA), in all consecutive AF patients discharged from NOACs from the Cardiology Division of a main city hospital between February 1st and May 31st 2018. We compared the different estimates of glomerular filtration rate and potential renal function class misclassifications. We reclassified 37/115 patients (32.1%) when switching from the CG to the CKD-EPI, and 24/115 (20.8%) switching from the CG to the CKD-EPI_noBSA formulas. Class reallocation was distributed across all levels of renal function, but mostly affected the &ldquo, hyper-normal&rdquo, function. In estimating consequences of such reallocation, a change in NOAC dosages would have occurred in 10/115 patients (8.7%) when switching from the CG to the CKD-EPI formula and in 10/115 patients when switching from the CG to the CKD-EPI_noBSA formula. Although the CG method has been traditionally used to calculate renal function in all NOAC studies, a renal dysfunction class reallocation occurs in a substantial fraction of hospital-admitted AF patients with the use of better estimates of renal function.

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability. Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence. Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy. We tested each SNP for both association and linkage with MS, the linkage being explored in terms of identity-by-descent (IBD) sharing excess and using gene dropping to compute a corresponding empirical p-value. By targeting regions that are both associated and in linkage with MS, we increase chances of identifying interesting genomic regions. Results: We identified 486 MS-associated ( p –4) and 18,426 MS-linked ( p Conclusion: We discovered new suggestive signals and confirmed some previously identified ones. We believe this to represent a significant step toward an understanding of the genetic basis of MS.

Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson’s disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. SH-SY5Y cells with a stable knockdown of Parkin or SLP-2, as well as induced pluripotent stem cell-derived neurons from Parkin mutation carriers, showed decreased complex I activity and altered mitochondrial network morphology. Importantly, induced expression of SLP-2 corrected for these mitochondrial alterations caused by reduced Parkin function in these cells. In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes, in particular loss of dopaminergic neurons, mitochondrial network structure, reduced ATP production, and flight and motor dysfunction. The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

BACKGROUND Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.OBJECTIVES This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.METHODS Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 +/- 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.RESULTS Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.CONCLUSIONS The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms. (C) 2019 by the American College of Cardiology Foundation.

In this trans-ethnic multi-omic study we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenome, and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in GWASs of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically-predicted gene expression of 840 genes in 45 tissues, and murine renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells., Editorial summary: Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.

Background: Lipids are increasingly involved in cardiovascular risk prediction as potential proarrhythmic influencers. However, knowledge is limited about the specific mechanisms connecting lipid alterations with atrial conduction. Methods: To shed light on this issue, we conducted a broad assessment of 151 sphingo- and phospholipids, measured using mass spectrometry, for association with atrial conduction, measured by P wave duration (PWD) from standard electrocardiograms, in the MICROS study (Microisolates in South Tyrol) (n=839). Causal pathways involving lipidomics, body mass index (BMI), and PWD were assessed using 2-sample Mendelian randomization analyses based on published genome-wide association studies of lipidomics (n=4034) and BMI (n=734 481), and genetic association analysis of PWD in 5 population-based studies (n=24 236). Results: We identified an association with relative phosphatidylcholine 38:3 (%PC 38:3) concentration, which was replicated in the ORCADES (Orkney Complex Disease Study; n=951), with a pooled association across studies of 2.59 (95% CI, 1.3–3.9; P =1.1×10 −4 ) ms PWD per mol% increase. While being independent of cholesterol, triglycerides, and glucose levels, the %PC 38:3-PWD association was mediated by BMI. Results supported a causal effect of BMI on both PWD ( P =8.3×10 −5 ) and %PC 38:3 ( P =0.014). Conclusions: Increased %PC 38:3 levels are consistently associated with longer PWD, partly because of the confounding effect of BMI. The causal effect of BMI on PWD reinforces evidence of BMI’s involvement into atrial electrical activity.

BackgroundHeart rate variability (HRV) reflects the autonomous nervous system modulation on heart rate and is associated with several pathologies, including cardiac mortality. While mechanistic studies show that smoking is associated with lower HRV, population-based studies present conflicting results.MethodsWe assessed the mutual effects of active smoking status, cumulative smoking history, and current smoking intensity, on HRV among 4751 adults from the Cooperative Health Research In South Tyrol (CHRIS) study. The HRV metrics standard deviation of normal-to-normal (NN) inter-beat intervals (SDNN), square root of the mean squared differences of consecutive NN intervals (RMSSD), total power (TP), low (LF) and high frequency (HF) power, and their ratio (LF/HF), were derived from 20-minute electrocardiograms. Smoking status, pack-years (PY), and tobacco grams/day from standardized questionnaires were the main exposures. We fitted linear mixed models to account for relatedness, non-linearity, and moderating effects, and including fractional polynomials.ResultsPast smokers had higher HRV levels than never smokers, independently of PY. The association of HRV with current smoking became apparent when accounting for the interaction between smoking status and PY. In current smokers, but not in past smokers, we observed HRV reductions between 2.0% (SDNN) and 4.9% (TP) every 5 PY increase. Furthermore, current smokers were characterized by dose-response reductions of 9.8% (SDNN), 8.9% (RMSSD), 20.1% (TP), 17.7% (LF), and 19.1% (HF), respectively, every 10 grams/day of smoked tobacco, independently of common cardiometabolic conditions and HRV-modifying drugs. The LF/HF ratio was not associated with smoking status, history, or intensity.ConclusionsSmoking cessation was associated with higher HRV levels. In current smokers, heavier smoking intensity appears gradually detrimental on HRV, corroborating previous evidence. By affecting both the sympathetic and parasympathetic nervous system indexes, but not the LF/HF balance, smoking intensity seems to exert a systemic dysautonomic effect.

Objective: The aims of the present study were to profile the expression of several candidate microRNAs (miRNAs) in blood from l-dopa-treated and drug-naive patients with Parkinson disease (PD) vs unaffected controls and to interpret the miRNA expression data in a biological context. Methods: We analyzed RNAs from peripheral blood of 36 l-dopa–treated, 10 drug-naive patients with PD and unaffected controls matched 1:1 by sex and age. We evaluated expression by reverse transcription–quantitative real-time PCR, and we analyzed data using a 2-tailed paired t test. To detect miRNA targets, several miRNA resources were combined to generate an overall score for each candidate gene using weighted rank aggregation. Results: Significant overexpression of miR-103a-3p ( p p = 0.002), and miR-29a-3p ( p = 0.005) in treated patients with PD was observed, and promising candidate target genes for these were revealed by an integrated in silico analysis. Conclusions: We revealed 3 candidate biomarkers for PD. miRNAs 30b-5p and 29a-3p replicated a documented deregulation in PD albeit opposite to published data, while for miR-103a-3p, we demonstrated for the first time an overexpression in treated patients with PD. Expression studies in patients and/or in isolated peripheral blood mononuclear cells before and after l-dopa administration are necessary to define the involvement of l-dopa treatment in the observed overexpression. Our in silico analysis to prioritize targets of deregulated miRNAs identified candidate target genes, including genes related to neurodegeneration and PD. Despite the preliminary character of our study, the results provide a rationale for further clarifying the role of the identified miRNAs in the pathogenesis of PD and for validating their diagnostic potential.

Background— Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. Methods and Results— We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was Conclusions— In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal.

In genetic association studies, a single marker is often associated with multiple, correlated phenotypes (e.g., obesity and cardiovascular disease, or nicotine dependence and lung cancer). A pervasive question is then whether that marker exerts independent effects on all phenotypes. In this paper, we address this question by assessing whether there is a genetic effect on one phenotype that is not mediated through the other ones, so called direct genetic effect. Answering such question may represent an important step in the elucidation of the underlying biological mechanism. Under rather restrictive conditions, such direct genetic effects are known to be estimable by standard regression methods. Under more lenient conditions, in a prospective or unmatched case-control study, these effects can be estimated by using a previously proposed G-estimation method (Vansteelandt [2009] Epidemiology 20, 851-860). The present paper extends this method to matched case-control studies, and investigates the conditions under which this extension is valid. We illustrate the method on data from a matched case-control study, which we use to elucidate the pathway implications of a detected association between myocardial infarction and a genetic locus in the chromosomal region of the FTO gene.

Genomewide studies of genetic association may prove less useful for individual risk estimation than for discovering and characterizing pathogenetic molecular pathways (Hirschhorn, 2009). In the latter task, they complement the traditional tools of bioinformatics and experimental biology. They contribute the empirical muscle that only the epidemiological observation of the disease process in humans may provide. This chapter illustrates this with the aid of a study of the types of ion channel dysfunction that may cause multiple sclerosis (MS). From a methodological point of view, this chapter complements Chapter 14 in this volume by tackling a form of interaction where the value of a causal factor determines a change of direction in the effect of another factor (Azzalini and Cox, 1984). This form of interaction, known as qualitative, is interpretable in terms of mechanism. We propose a method for testing for qualitative interaction between genetic effects, in the context of the analysis of family structured genetic data. We illustrate the method with the aid of the above mentioned study.

BACKGROUND Contrasting data have been reported on the association between the presence of anti-phospholipid antibodies (aPL) and arterial thrombotic events, particularly those in coronary arteries. This discrepancy is perhaps related to the confounding effect of traditional risk factors. Among them, coronary atherosclerosis appears to be the most important in studies conducted in middle-aged and elderly patients. OBJECTIVE To minimize such confounding effects, a multicenter case-control study on the association between aPL and myocardial infarction (MI) was carried out in a rare cohort of young premenopausal women. METHODS We evaluated 172 cases hospitalized for a first MI before the age of 45 years and 172 controls individually matched with cases for age, sex and geographical origin. Clinical and laboratory data were collected and levels of anti-cardiolipin (aCL), anti-beta2 glycoprotein I (anti-beta2GPI) and anti-nuclear antibodies (ANA) were measured. RESULTS A significant association between MI and IgG/IgM anti-beta2GPI antibodies was observed; the results were confirmed after adjusting for smoking and hypertension (anti-beta2GPI IgG OR = 2.47, 95% CI 1.81-3.38; anti-beta2GPI IgM 4th quartile OR 3.68, 95% CI 1.69-8.02). The association between anti-beta2GPI antibodies and MI was detected in both subgroups with and without coronary artery stenosis. Whereas the association of aCL IgG with MI was modest, ANA showed no significant association with MI. No aPL were found in unselected patients (mainly males) who recently developed acute MI. CONCLUSIONS Anti-beta2GPI antibodies are a significant risk factor for MI in young premenopausal women independently of other risk factors, including the degree of coronary artery stenosis.

Women who develop acute myocardial infarction (AMI) at a young age have fewer classical risk factors and less coronary stenosis than older women. In this rare population, it is plausible that a heightened hemostatic system may play an important mechanistic role in thrombus formation and in the development of AMI. We chose to investigate whether or not there is an association between premature AMI and the plasma concentrations of five hemostatic measurements that had been previously established as risk factors for AMI, and of the inflammation marker C-reactive protein (CRP). Women who had survived AMI at the age of 45 years or less (n = 141) were drawn from those admitted to 125 Italian coronary care units over a 3-year period. In them, and in an equal number of controls, plasma levels of immunoreactive tissue plasminogen activator (tPA), plasminogen activation inhibitor 1 (PAI-1), von Willebrand factor (VWF), fibrinogen, D-dimer and CRP were measured. Higher levels of VWF, fibrinogen, CRP and tPA were associated with AMI. After adjustment for both classical and hemostatic risk factors, only tPA maintained an independent association with AMI: the odds ratios (taken as an index of relative risk) for tPA values in the middle and higher tertiles were 2.86 (CI 1.63-5.02) and 8.18 (CI 2.66-25.20), respectively. In conclusion, there is a strong association between non-fatal AMI and increased plasma levels of tPA antigen. This finding is thought to be the expression of a reduced rather than enhanced fibrinolytic activity.