Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries.

We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP density and annotation information, suggesting whole-genome sequence variants with annotations may further improve prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from nonsynonymous SNPs.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

A genome-wide association study of 24-hour urinary excretion of endocrine disrupting chemicals.

Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem, but much remains unknown on the inter-individual differences in metabolism and excretion of EDCs. To examine this we performed a two-stage genome-wide association study (GWAS) for 24-hour urinary excretions of four parabens, two bisphenols, and nine phthalate metabolites. Results showed five genome-wide significant (p-value < 5x10-8) and replicated single nucleotide polymorphisms (SNPs) representing four independent signals that associated with mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Three of the four signals were located on chromosome 10 in a locus harboring the cytochrome P450 (CYP) genes CYP2C9, CYP2C58P, and CYP2C19 (rs117529685, pMECPP = 5.38x10-25; rs117033379, pMECPP = 1.96x10-19; rs4918798, pMECPP = 4.01x10-71; rs7895726, pMEHHP = 1.37x10-15, r2 with rs4918798 = 0.93). The other signal was on chromosome 6 close to the solute carrier (SLC) genes SLC17A1, SLC17A3, SLC17A4, and SCGN (rs1359232, pMECPP = 7.6x10-16). These four SNPs explained a substantial part (8.3 % - 9.2 %) of the variance in MECPP in the replication cohort. Bioinformatics analyses supported a likely causal role of CYP2C9 and SLC17A1 in metabolism and excretion of MECPP and MEHHP. Our results provide biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9 and SLC17A1.

Phenotypic but not genetically predicted heart rate variability associated with all-cause mortality.

Low heart rate variability (HRV) has been widely reported as a predictor for increased mortality. However, the molecular mechanisms are poorly understood. Therefore, this study aimed to identify novel genetic loci associated with HRV and assess the association of phenotypic HRV and genetically predicted HRV with mortality. In a GWAS of 46,075 European ancestry individuals from UK biobank, we identified 17 independent genome-wide significant genetic variants in 16 loci associated with HRV traits. Notably, eight of these loci (RNF220, GNB4, LINCR-002, KLHL3/HNRNPA0, CHRM2, KCNJ5, MED13L, and C160rf72) have not been reported previously. In a prospective phenotypic relationship between HRV and mortality during a median follow-up of seven years, individuals with lower HRV had higher risk of dying from any cause. Genetically predicted HRV, as determined by the genetic risk scores, was not associated with mortality. To the best of our knowledge, the findings provide novel biological insights into the mechanisms underlying HRV. These results also underline the role of the cardiac autonomic nervous system, as indexed by HRV, in predicting mortality.

Familial co-aggregation and shared genetics of cardiometabolic disorders and traits: data from the multi-generational Lifelines Cohort Study.

BACKGROUND: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study. METHODS: We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λR) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h2), shared environment, and genetic correlation (rg) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age2, and sex. RESULTS: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λFDR of 1.23 (95% CI 1.20-1.25) for hypertension to λFDR of 2.48 (95% CI 2.15-2.86) for T2D. Most of these were higher than in spouses (λSpouses < λFDR), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h2CRP: 0.26 to h2HDL: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λFDR obesity-MetS: 1.28 (95% CI 1.24-1.32) to λFDR MetS-T2D: 1.61 (95% CI 1.52-1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from rg HDL-Triglycerides: - 0.53 to rg LDL-Apolipoprotein B: 0.94). CONCLUSIONS: There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.

A multidimensional longitudinal dataset on functional somatic syndromes.

Functional disorders represent a prevalent health issue, significantly impacting both individuals and healthcare systems. This multidisciplinary dataset aims to enhance our comprehension of the complex interplay among various factors that contribute to functional somatic syndromes. The dataset comprises data from seemingly healthy adults (aged 18-65) in Isfahan, Iran, who were randomly selected and monitored for four consecutive years. The research data encompasses seven distinct datasets: (a) functional symptom evaluations across multiple body organs, (b) psychological assessments, (c) lifestyle factors, (d) demographic and socioeconomic variables, (e) laboratory measurements, (f) clinical examinations, and (g) historical information. A total of 1930 participants were enrolled at the study's outset in 2017. The first, second, and third annual follow-up rounds were completed with 1697 (2018), 1616 (2019), and 1176 (2020) participants, respectively. This dataset is made available for further analysis by a diverse range of researchers, healthcare policymakers, and clinicians.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Multidisciplinary approach to functional somatic syndromes: study protocol for a population-based prospective cohort study.

INTRODUCTION: Isfahan functional disorders (ISFUN) cohort study aims to describe the interplay of genetic and environmental factors in shaping the characteristics of functional somatic syndromes (FSS). This study is primarily intended to investigate the epidemiology, risk factors, course and prognosis of FSSs in a sample of adult Iranian population. The other aim is to develop a new delimitation of FSSs based on an integrated multidisciplinary approach comprising of phenotypic and multiomics data. METHODS AND ANALYSIS: ISFUN is a population-based prospective cohort study designed to follow a population of randomly selected seemingly healthy adults (18-65 years) through annual visits during a 4-year observation period. Structured questionnaires are used for data collection and clinical assessment of the participants. Questionnaire-based diagnosis of FSSs are validated in a medical interview. Human DNA genotyping, microbial amplicon sequencing and urine analysis is under progress for genomics, microbiota and metabolomics profiling, respectively. Enrolment began in September 2017, and study completion is expected in 2022. A total number of 1943 participants were initially recruited. ETHICS AND DISSEMINATION: Ethical approval for data collection was granted by the National Research Ethics Committee of the Iranian Ministry of Health and Medical Education and the Research Ethics Committee of Isfahan University of Medical Sciences (IR.MUI.REC.1395.1.149). Following the description of the study procedure, we obtained written informed consent from all study participants. Study findings will be disseminated through peer-reviewed publications and presentations at scientific meetings.

Increased genetic contribution to wellbeing during the COVID-19 pandemic.

Physical and mental health are determined by an interplay between nature, for example genetics, and nurture, which encompasses experiences and exposures that can be short or long-lasting. The COVID-19 pandemic represents a unique situation in which whole communities were suddenly and simultaneously exposed to both the virus and the societal changes required to combat the virus. We studied 27,537 population-based biobank participants for whom we have genetic data and extensive longitudinal data collected via 19 questionnaires over 10 months, starting in March 2020. This allowed us to explore the interaction between genetics and the impact of the COVID-19 pandemic on individuals' wellbeing over time. We observe that genetics affected many aspects of wellbeing, but also that its impact on several phenotypes changed over time. Over the course of the pandemic, we observed that the genetic predisposition to life satisfaction had an increasing influence on perceived quality of life. We also estimated heritability and the proportion of variance explained by shared environment using variance components methods based on pedigree information and household composition. The results suggest that people's genetic constitution manifested more prominently over time, potentially due to social isolation driven by strict COVID-19 containment measures. Overall, our findings demonstrate that the relative contribution of genetic variation to complex phenotypes is dynamic rather than static.

GWASinspector: comprehensive quality control of genome-wide association study results.

SUMMARY: Quality control (QC) of genome wide association study (GWAS) result files has become increasingly difficult due to advances in genomic technology. The main challenges include continuous increases in the number of polymorphic genetic variants contained in recent GWASs and reference panels, the rising number of cohorts participating in a GWAS consortium, and inclusion of new variant types. Here, we present GWASinspector, a flexible R package for comprehensive QC of GWAS results. This package is compatible with recent imputation reference panels, handles insertion/deletion and multi-allelic variants, provides extensive QC reports and efficiently processes big data files. Reference panels covering three human genome builds (NCBI36, GRCh37 and GRCh38) are available. GWASinspector has a user friendly design and allows easy set-up of the QC pipeline through a configuration file. In addition to checking and reporting on individual files, it can be used in preparation of a meta-analysis by testing for systemic differences between studies and generating cleaned, harmonized GWAS files. Comparison with existing GWAS QC tools shows that the main advantages of GWASinspector are its ability to more effectively deal with insertion/deletion and multi-allelic variants and its relatively low memory use. AVAILABILITY AND IMPLEMENTATION: Our package is available at The Comprehensive R Archive Network (CRAN): https://CRAN.R-project.org/package=GWASinspector. Reference datasets and a detailed tutorial can be found at the package website at http://gwasinspector.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population.

BACKGROUND: Serum calciprotein particle maturation time (T50), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T50 and study their association with cardiovascular disease and mortality. METHODS: We performed a genome-wide association study of serum T50 in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T50 on cardiovascular outcomes. Finally, we examined associations between T50 loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. RESULTS: We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10-101), rs2077119 (p = 3.34 × 10-18), and rs9870756 (p = 3.10 × 10-8), together explaining 18.3% of variation in serum T50. MR did not demonstrate a causal effect of T50 on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T50, was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01-1.28)] and all-cause mortality alone [1.14 (1.00-1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06-1.84), relative excess risk due to interaction 0.54 (0.01-1.08)]. CONCLUSIONS: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T50 levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.

Renal transplantation in allografts with multiple versus single renal arteries.

Allograft with multiple renal arteries (MRA) is considered to have an increased post-transplantation risk due to vascular and urologic complications. The aim of this study is to investigate the outcome of living donor kidney transplantation using allograft with a single artery and recipients of allografts with multiple arteries. Seven hundred and eighteen consecutive adult kidney transplants done between 1998 and 2007, with living unrelated kidney donors, were enrolled in this retrospective analysis. Data from the group with MRA (n = 60) were compared with those from the group with single renal artery (SRA) (n = 658). Delayed graft function (DGF) was more frequent in recipients' allografts with more than 2 arteries when compared with SRA recipients (Odds Ratio: 1.2; 95% CI:1.08-1.9, P = 0.02), but there was no difference between SRA and allograft with two arteries. The incidence of acute rejection (AR) was not statistically greater in recipients with MRA. Renal artery stenosis (RAS) occurred more frequently in patients with MRA (8.3% vs. 5.9% and P = 0.02), but other vascular complications such as renal artery thrombosis and hematoma revealed no differences (P > 0.05). Urologic complications such as UVJ obstruction, urinary leakage and ureteropelvic obstruction were not statistically different between the groups. The actuarial 1-year allograft survival rate was comparable in both groups (93.6% vs 96.8%, P = 0.22). Allografts with more than two arteries were associated with increased DGF and RAS, but no surgical or urological complications were detected in our series. Our findings demonstrate that renal allograft transplantation with multiple arteries could be performed with reasonable complications and acceptable outcomes.

Correlation between the degree of air trapping in chest HRCT and cardiopulmonary exercise test parameters: could HRCT be a predictor of disease severity?

OBJECTIVE: The purpose of this study was to examine whether the degree of air trapping in high resolution computed tomography (HRCT) of patients with histories of sulfur mustard gas exposure during suspended full expiration correlated with various parameters of the cardiopulmonary exercise test as the gold standard for assessment of pulmonary function. METHODS: In this analytic study 75 male patients, each with a history of sulfur mustard gas exposure, were investigated. Each participant underwent an incremental cardiopulmonary exercise test, pulmonary function test and arterial oxygen saturation for hemoglobin measurement. For HRCT examination, both lungs were divided into three parts (upper, middle, and lower) and in each part images were separately observed from the involved area point of view (<25% ≤6/24; >25% ≥6/24). RESULTS: A total of 49.3% of the patients (37/75) had evidence of air trapping in over 25% of their lung segments. The mean age±SD in the patients with air trapping of =25% or <25% were 41.1±6.8 and 39.7±4.0 years, respectively (P=0.281). In our study there was no significant difference in pulmonary function test findings (FEV1, FVC and FEV1/FVC) between the two groups. There was no significant correlation with air trapping of =25% and any of the exercise test parameters. Also, no correlation was found between significant air trapping and exercise test findings in maximum exercise and anaerobic situations. CONCLUSIONS: No correlation was found between HRCT and cardiopulmonary exercise test findings. HRCT is neither pathognomic of the disease nor a good predictor of disease severity but it might be suggestive of mustard lung injuries.

Effect of titanium on lipoprotein lipase activity in vivo and in vitro.

SUMMARY: Lipoprotein lipase (LPL) is a major lipolytic enzyme in the intravascular metabolism of postprandial triglyceride-rich lipoproteins. This enzyme is synthesized and secreted by tissues and transported to the capillary endothelial surface. Decreased activity of this enzyme is suggested to be involved in arterial sequestration of lipoproteins and thus in the progression of atherosclerosis. Titanium salts are widely used in industry, medicine, and pharmacy for tablet coating, pharmaceuticals and cosmetic products. In this study the effect of titanium on post-heparin LPL activity is reported in vivo and in vitro. METHODS: Groups of Male Wistar rats were administered (i.p) with an acute dose of 2.5 mg/kg titanium chloride for 10 days and a chronic dose of 0.75 mg/kg for 30 and/or 60 days. Blood samples were then collected for LPL assay. For in vitro study, plasma aliquots were incubated in the presence of up to 50 mM titanium and the enzyme activity was measured. RESULTS: Animals exposed to acute dose of titanium showed about 20% reduction in LPL activity, whereas 31% and 36% reductions were observed in animals chronically exposed for 30 and/or 60 days, respectively. Titanium in vitro also led to enzyme inhibition, so that a decrease of 28-53% was seen in the presence of 0.1-50 mM titanium. This inhibition by titanium was potentiated when citrate and/or bicarbonate was present. CONCLUSION: Although the mechanism of titanium effect on LPL activity in vivo and in vitro demands more investigations, the inhibitory effect of titanium ion in vivo should be considered seriously in subjects exposed to this metal ion. Changes in LPL activity may affect whole body lipid metabolism, a condition favorable for development and progression of atherosclerosis.