ORCID Profile
0000-0002-2581-484X
Current Organisations
Lund University, Medical Faculty
,
Skåne University Hospital
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Publications
Alcohol intake in relation to non-fatal and fatal coronary heart disease and stroke: EPIC-CVD case-cohort study
Publisher: BMJ
Date: 29-05-2018
DOI: 10.1136/BMJ.K934
Abstract: To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke. Multicentre case-cohort study. A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries. 32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison. Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke). There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events. Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.
The Effect of Menopause on Carotid Artery Remodeling, Insulin Sensitivity, and Plasma Adiponectin in Healthy Women
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1038/AJH.2009.16
Abstract: The mechanisms by which menopause may influence the systemic subclinical atherosclerosis are unexplained. The aim of this cross-sectional study was to evaluate the associations between early menopause, established cardiovascular (c-v) risk factors, metabolic parameters (insulin secretion and sensitivity, plasma adiponectin), and carotid intima-media thickness (IMT) in healthy women. In 74 menopausal women (mean age = 51 +/- 3 years, mean duration of menopause = 2.9 +/- 1.2 years) and in 74 nonmenopausal women comparable for age and body mass index (BMI), common carotid artery (CCA) luminal diameter, and IMT in different carotid segments were measured in digitized ultrasound images. Insulin sensitivity and secretion were assessed using the euglycemic hyperinsulinemic cl technique and oral glucose tolerance test (OGTT). Insulin secretion was reconstructed by mathematical modeling. CCA diameter (5.55 +/- 0.46 vs. 5.21+/- 0.51 mm, P < 0.001), CCA IMT (608 +/- 78 vs. 576 +/- 74 microm, P < 0.01) and systolic blood pressure (BP) (117 +/- 12 vs. 113 +/- 11 mm Hg, P < 0.05) were higher in menopausal women, whereas CCA IMT/diameter ratio and IMT in other carotid segments did not differ between the groups. By multivariate models, independent predictors of CCA diameter were menopause and body weight (cumulative R2 = 0.37) and independent correlates of CCA IMT were luminal diameter, systolic BP and low-density lipoprotein (LDL) cholesterol (cumulative R2 = 0.48). Fasting insulin, insulin secretion, and sensitivity and plasma adiponectin were similar in the two groups and were not related to carotid IMT. Early menopause is associated with CCA remodeling, characterized by a proportional increase in luminal diameter and wall thickness, independent of atherosclerotic risk factors and metabolic variables.
The mutational constraint spectrum quantified from variation in 141,456 humans
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41586-020-2308-7
Abstract: Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large s le sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
A catalog of genetic loci associated with kidney function from analyses of a million individuals
Publisher: Springer Science and Business Media LLC
Date: 25-11-2027
Seventy-five genetic loci influencing the human red blood cell
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Atrial Fibrillation Genetic Risk Differentiates Cardioembolic Stroke from other Stroke Subtypes
Publisher: Cold Spring Harbor Laboratory
Date: 24-12-2017
DOI: 10.1101/239269
Abstract: We sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk. We evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p 4.4 × 10 −4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10 −48 ), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p 0.1). Genetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium
Publisher: Elsevier BV
Date: 12-2019
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1038/S41598-017-03054-8
Abstract: Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS , which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1 , BBS9 , GNAS , MKKS , CLOCK and ANGPTL6 . The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 −3 ), highlighting the challenges of testing rare variant associations and the need for very large s le sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.
The effect of LRRK2 loss-of-function variants in humans
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41591-020-0893-5
Abstract: Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes 1,2 . Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease 3,4 , suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns 5–8 , the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 in iduals sequenced in the Genome Aggregation Database (gnomAD) 9 , 49,960 exome-sequenced in iduals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 in iduals with high-confidence pLoF variants in LRRK2 . Experimental validation of three variants, combined with previous work 10 , confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2019
DOI: 10.1212/WNL.0000000000006851
Abstract: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up s le or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy. In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
2-Aminoadipic acid is a biomarker for diabetes risk
Publisher: American Society for Clinical Investigation
Date: 16-09-2013
DOI: 10.1172/JCI64801
Interaction of dietary and genetic factors influencing body iron status and risk of type 2 diabetes within the EPIC-InterAct study
Publisher: American Diabetes Association
Date: 22-11-2018
DOI: 10.2337/DC17-1080
Abstract: Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes. The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression. Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082 0.144]), but not with transferrin (−0.019 [−0.043 0.006]) or transferrin saturation (0.016 [−0.006 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6 V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population (Padd = 0.16, Pmult = 0.21) but did detect a trend toward a negative interaction in men (Padd = 0.04, Pmult = 0.03). We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two in idual exposures.
Defining the role of common variation in the genomic and biological architecture of adult human height
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
Publisher: American Diabetes Association
Date: 27-04-2018
DOI: 10.2337/DB17-0914
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication s les, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased s le sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
Publisher: Springer Science and Business Media LLC
Date: 12-06-2017
DOI: 10.1038/NG.3892
The genomics of heart failure: design and rationale of the HERMES consortium
Publisher: Wiley
Date: 03-09-2021
DOI: 10.1002/EHF2.13517
Abstract: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological s les and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 in idual studies enrolled participants of both sexes in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate s le, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P 5 × 10 −8 under an additive genetic model. HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization and (iii) develop genomic tools for disease stratification and risk prediction.
Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
Publisher: Elsevier BV
Date: 03-2020
Pathogenic Ischemic Stroke Phenotypes in the NINDS-Stroke Genetics Network
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/STROKEAHA.114.007362
Abstract: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. The distribution of pathogenic categories varied by study, age, sex, and race ( P .001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72 95% confidence interval, 0.69–0.75) and phenotypic classifications (κ 0.73 95% confidence interval, 0.70–0.75). This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.
A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study
Publisher: Public Library of Science (PLoS)
Date: 11-10-2017
The Swedish CArdioPulmonary BioImage Study: objectives and design
Publisher: Wiley
Date: 19-06-2015
DOI: 10.1111/JOIM.12384
Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD
Publisher: Elsevier BV
Date: 11-2017
A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium
Publisher: Springer Science and Business Media LLC
Date: 11-10-2009
DOI: 10.1038/NG.467
Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
Publisher: Elsevier BV
Date: 11-2012
A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
Publisher: Oxford University Press (OUP)
Date: 14-03-2018
DOI: 10.1093/HMG/DDY094
Fasting insulin has a stronger association with an adverse cardiometabolic risk profile than insulin resistance: the RISC study
Publisher: Oxford University Press (OUP)
Date: 08-2009
DOI: 10.1530/EJE-09-0058
Abstract: Fasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis. The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort consists of 1326 European non-diabetic, overall healthy men and women aged 30–60 years. We performed standard oral glucose tolerance tests and hyperinsulinemic euglycemic cl s. As a general measure of cardiovascular risk, we assessed the prevalence of the metabolic syndrome in 1177 participants. Carotid artery intima media thickness (IMT) was measured by ultrasound to assess preclinical atherosclerosis. Fasting insulin was correlated with all elements of the metabolic syndrome. Insulin sensitivity ( M / I ) was correlated with most elements. The odds ratio for the metabolic syndrome of those in the highest quartile of fasting insulin compared with those in the lower quartiles was 5.4 (95% confidence interval (CI) 2.8–10.3, adjusted for insulin sensitivity) in men and 5.1 (2.6–9.9) in women. The odds ratio for metabolic syndrome of those with insulin sensitivity in the lowest quartile of the cohort compared with those in the higher quartiles was 2.4 (95% CI 1.3–4.7, adjusted for fasting insulin) in men and 1.6 (0.8–3.1) in women. Carotid IMT was only statistically significantly associated with fasting insulin in both men and women. Fasting insulin, a simple and practical measure, may be a stronger and independent contributor to cardiometabolic risk and atherosclerosis in a healthy population than hyperinsulinemic euglycemic cl -derived insulin sensitivity.
Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci
Publisher: Elsevier BV
Date: 03-2014
Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2013
Abstract: Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type–restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type–specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type–restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates
Publisher: Public Library of Science (PLoS)
Date: 31-10-2013
Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2020
DOI: 10.1101/2020.04.03.023804
Abstract: Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 in iduals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping using trans -pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of in iduals enabling precision medicine.
Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations
Publisher: Elsevier BV
Date: 07-2014
Mendelian randomization of blood lipids for coronary heart disease
Publisher: Oxford University Press (OUP)
Date: 28-01-2014
C-peptide predicts all-cause and cardiovascular death in a cohort of individuals with newly diagnosed type 2 diabetes. The Skaraborg diabetes register
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.DIABRES.2019.03.014
Abstract: To study the association between baseline level of C-peptide and all-cause death, cardiovascular death and cardiovascular complications among persons with newly diagnosed type 2 diabetes. The Skaraborg Diabetes Register contains data on baseline C-peptide concentrations among 398 persons <65 years with newly diagnosed type 2 diabetes 1996-1998. National registries were used to determine all-cause death, cardiovascular death and incidence of myocardial infarction and ischemic stroke until 31 December 2014. The association between baseline C-peptide and outcomes were evaluated with adjustment for multiple confounders by Cox regression analysis. Missing data were handled by multiple imputation. In the imputed and fully adjusted model there was a significant association between 1 nmol/l increase in C-peptide concentration and all-cause death (HR 2.20, 95% CI 1.49-3.25, p < 0.001, number of events = 104), underlying cardiovascular death (HR 2.69, 1.49-4.85, p = 0.001, n = 35) and the composite outcome of underlying cardiovascular death, myocardial infarction or ischemic stroke (HR 1.61, 1.06-2.45, p = 0.027, n = 90). Elevated C-peptide levels at baseline in persons with newly diagnosed type 2 diabetes are associated with increased risk of all-cause and cardiovascular mortality. C-peptide might be used to identify persons at high risk of cardiovascular complications and premature death.
GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
DOI: 10.1038/S41467-018-07340-5
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 in iduals for cIMT, and 48,434 in iduals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Stroke Genetics Network (SiGN) Study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
DOI: 10.1161/STROKEAHA.113.001857
Abstract: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
Sex‐Specific Effects of Adiponectin on Carotid Intima‐Media Thickness and Incident Cardiovascular Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-08-2015
Abstract: Plasma adiponectin levels have previously been inversely associated with carotid intima‐media thickness ( IMT ), a marker of subclinical atherosclerosis. In this study, we used a sex‐stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT . Baseline plasma adiponectin concentration was tested for association with baseline IMT , IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777 men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (β=−0.018, P .001) in men but not in women (β=−0.006, P =0.185 P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (β=−0.0022, P =0.047), whereas no association was seen in women (0.0007, P =0.475 P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82, 95% CI 0.54 to 1.25). A gene score of adiponectin‐raising alleles in 6 loci, reported recently in a large multi‐ethnic meta‐analysis, was inversely associated with baseline mean bifurcation IMT in men (β=−0.0008, P =0.004) but not in women (β=−0.0003, P =0.522 P for interaction=0.007). This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted.
Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41588-018-0297-3
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
Publisher: Springer Science and Business Media LLC
Date: 23-11-2020
Author Correction: A structural variation reference for medical and population genetics
Publisher: Springer Science and Business Media LLC
Date: 03-02-2021
DOI: 10.1038/S41586-020-03176-6
Abstract: A Correction to this paper has been published: 0.1038/s41586-020-03176-6.
Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humans
Publisher: Springer Science and Business Media LLC
Date: 03-02-2021
DOI: 10.1038/S41586-020-03174-8
Abstract: A Correction to this paper has been published: 0.1038/s41586-020-03174-8.
Influence of the ACE Gene Insertion/Deletion Polymorphism on Insulin Sensitivity and Impaired Glucose Tolerance in Healthy Subjects
Publisher: American Diabetes Association
Date: 04-2008
DOI: 10.2337/DC07-1788
Abstract: OBJECTIVE—Recent studies suggested that the blockade of the renin-angiotensin system (RAS) may be associated with metabolic benefits. However, data about the potential influence of the ACE insertion/deletion (I/D) genotype on insulin resistance have been contradictory with studies of limited s le sizes. The purpose of this study was to investigate the relationship between the ACE gene I/D polymorphism and both insulin sensitivity and glucose intolerance in a large cohort of healthy subjects. RESEARCH DESIGN AND METHODS—A total of 1,286 participants in the Relationship Between Insulin Sensitivity and Cardiovascular Disease Risk Study had a 75-g oral glucose tolerance test and a hyperinsulinemic-euglycemic cl to assess whole-body insulin sensitivity. RESULTS—Age, BMI, waist, fat-free mass (ffm), and physical activity did not differ by ACE genotype. Fasting glucose and insulin were similar among genotypes, but 2-h glucose levels were higher in DD than in ID and II subjects (DD: 5.9 ± 1.7 ID: 5.7 ± 1.5 II: 5.6 ± 1.5 mmol/l) (P = 0.004). Participants with the DD genotype were more likely to have impaired glucose tolerance than those with the ID and II genotypes (13.1 vs. 8.7% P = 0.02). Insulin sensitivity was lower in participants with the DD genotype than in those with the II genotype (136 ± 63 vs. 147 ± 65 μmol · min−1· kg ffm−1 · mmol−1 · l−1 P = 0.02). The presence of the D allele was associated with a trend, albeit not significant, for reduced insulin secretion during the oral glucose tolerance test (P = 0.07). CONCLUSIONS—The ACE I/D polymorphism is associated with whole-body insulin sensitivity and with impaired glucose tolerance in our healthy population. These findings confirm potential interactions between the RAS and glucose metabolism.
Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
DOI: 10.1038/S41588-019-0449-0
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41467-019-10717-9
Abstract: Upstream open reading frames (uORFs) are tissue-specific cis -regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.
Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies
Publisher: Elsevier BV
Date: 04-2018
Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
Publisher: Springer Science and Business Media LLC
Date: 13-08-2018
DOI: 10.1038/S41467-018-05074-Y
Abstract: Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 in iduals and lung expression quantitative trait loci (eQTL) data on 409 in iduals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-01-2009
DOI: 10.1002/HEP.22845
Abstract: Patients with fatty liver (FL) disease have a high risk of developing diabetes and cardiovascular diseases. The aim was to evaluate the association between FL, insulin resistance (IR), coronary heart disease (CHD) risk, and early atherosclerosis in a large European population (RISC Study). In 1,307 nondiabetic subjects (age 30-60 years) recruited at 19 centers, we evaluated liver enzymes, lipids, insulin sensitivity (by euglycemic-hyperinsulinemic cl ), glucose tolerance (by 75 g oral glucose tolerance test), carotid atherosclerosis as intima media thickness (IMT), CHD risk by the Framingham Heart study prediction score, and physical activity (by accelerometer). The presence of FL was estimated using the fatty liver index (FLI >60, likelihood >78% presence FL FLI 91% absence of FL). Subjects were ided into three groups: G1: FLI 60 (n = 234), G2: intermediate group (n = 465). Compared to G1, G3 included more men (70% versus 24%) and people with impaired glucose tolerance (23% versus 5%). IMT increased with FLI (G3 = 0.64 +/- 0.08 versus G1 = 0.58 +/- 0.08 mm, P < 0.0001). FLI was associated with increased CHD risk (r = 0.48), low-density lipoprotein cholesterol (r = 0.33), alanine aminotransferase (r = 0.48), aspartate aminotransferase (r = 0.25), systolic blood pressure (r = 0.39) and IMT (r = 0.30), and reduced insulin sensitivity (r = -0.43), high-density lipoprotein cholesterol (r = -0.50), adiponectin (r = -0.42), and physical activity (r = -0.16, all P < 0.0001). The correlations hold also in multivariate analysis after adjusting for age, gender, and recruiting center. In middle-age nondiabetic subjects, increased IMT, CHD risk, and reduced insulin sensitivity are associated with high values of FLI.
Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.ATHEROSCLEROSIS.2020.01.011
Abstract: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease. In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up. In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061). Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.
Serum magnesium and calcium levels in relation to ischemic stroke
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-02-2019
Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies
Publisher: Oxford University Press (OUP)
Date: 22-11-2018
Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41467-019-12438-5
Abstract: Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an in idual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.
Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2019
DOI: 10.1101/682013
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide 1 . A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained 2–4 . We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development ( MYOZ1, SYNPO2L ), protein homeostasis ( BAG3 ), and cellular senescence ( CDKN1A ). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.
Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JACC.2018.09.085
Abstract: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. This study sought to test the association between the rs9349379 genotype and SCAD. Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
A structural variation reference for medical and population genetics
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41586-020-2287-8
Abstract: Structural variants (SVs) rearrange large segments of DNA 1 and can have profound consequences in evolution and human disease 2,3 . As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) 4 have become integral in the interpretation of single-nucleotide variants (SNVs) 5 . However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across erse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25–29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage 6 . We also uncovered modest selection against noncoding SVs in cis -regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of s les, and estimate that 0.13% of in iduals may carry an SV that meets the existing criteria for clinically important incidental findings 7 . This SV resource is freely distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data
Publisher: BMJ
Date: 10-07-2014
DOI: 10.1136/BMJ.G4164
Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses
Publisher: Elsevier BV
Date: 12-2021
Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
The genetic architecture of type 2 diabetes
Publisher: Springer Science and Business Media LLC
Date: 11-07-2016
DOI: 10.1038/NATURE18642
Author Correction: The effect of LRRK2 loss-of-function variants in humans
Publisher: Springer Science and Business Media LLC
Date: 22-01-2021
SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe
Publisher: Oxford University Press (OUP)
Date: 13-06-2021
DOI: 10.1093/EURHEARTJ/EHAB309
Abstract: The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in in iduals without previous CVD or diabetes aged 40–69 years in Europe. We derived risk prediction models using in idual-participant data from 45 cohorts in 13 countries (677 684 in iduals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 in iduals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 in iduals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65–0.68) to 0.81 (0.76–0.86). Predicted CVD risk varied several-fold across European regions. For ex le, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low-risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries. SCORE2—a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations—enhances the identification of in iduals at higher risk of developing CVD across Europe.
Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study
Publisher: Public Library of Science (PLoS)
Date: 08-06-2017
Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis
Publisher: Oxford University Press (OUP)
Date: 15-05-2015
DOI: 10.1093/IJE/DYV074
Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
Publisher: Springer Science and Business Media LLC
Date: 09-01-2020
DOI: 10.1038/S41467-019-13690-5
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development ( MYOZ1 , SYNPO2L ), protein homoeostasis ( BAG3 ), and cellular senescence ( CDKN1A ). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development
Publisher: Impact Journals, LLC
Date: 05-03-2019
Genetic loci influencing kidney function and chronic kidney disease
Publisher: Springer Science and Business Media LLC
Date: 11-04-2010
DOI: 10.1038/NG.566
Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
DOI: 10.1161/HYPERTENSIONAHA.111.181990
Abstract: Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37–1.73] combined P =2.58 · 10 −13 ). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25–1.44 P =1.032 · 10 −14 ). The quantitative analysis on a population-based s le revealed an effect size of 1.91 (95% CI: 0.16–3.66) for systolic and 1.40 (95% CI: 0.25–2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes
Publisher: American Society for Clinical Investigation
Date: 30-10-2017
DOI: 10.1172/JCI95995
Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks
Publisher: Elsevier BV
Date: 02-2014
Protein-altering germline mutations implicate novel genes related to lung cancer development
Publisher: Springer Science and Business Media LLC
Date: 11-05-2020
DOI: 10.1038/S41467-020-15905-6
Abstract: Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 in iduals of European ancestry and investigated gene expression levels in 7,773 s les. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 −15 ) and replication (adjusted OR = 2.93, P = 2.22 × 10 −3 ) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 −22 ) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930 . Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
Evaluating drug targets through human loss-of-function genetic variation
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41586-020-2267-Z
Abstract: Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous ‘knockout’ humans will await s le sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous in iduals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development.
Publisher Correction: Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
Publisher: Springer Science and Business Media LLC
Date: 16-03-2021
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
Publisher: Elsevier BV
Date: 04-2021
COL4A2 is associated with lacunar ischemic stroke and deep ICH
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2017
DOI: 10.1212/WNL.0000000000004560
Abstract: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. We meta-analyzed genotype data from in iduals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes ( COL4A1 , COL4A2 , NOTCH3 , HTRA1 , TREX1 , and CECR1 ) with intracerebral hemorrhage (ICH) (deep, lobar, all 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. A locus in COL4A2 was associated (significance threshold p 3.5 × 10 −4 ) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10 −8 ) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10 −5 ). A SNP in HTRA1 was associated (significance threshold p 5.5 × 10 −4 ) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10 −4 ) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype. These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
Association of Cardiometabolic Multimorbidity With Mortality
Publisher: American Medical Association (AMA)
Date: 07-07-2015
Genome-wide association study identifies eight loci associated with blood pressure
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-05-2021
DOI: 10.1161/ATVBAHA.120.315597
Abstract: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 in iduals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-s le Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke ( P =5.5×10 −7 ), which is in the opposite direction of the observational analyses. The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.
Eosinophil Cationic Protein, Carotid Plaque, and Incidence of Stroke
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2017
DOI: 10.1161/STROKEAHA.117.018450
Abstract: ECP (eosinophil cationic protein) is a marker of eosinophil activity and degranulation, which has been linked to atherosclerosis and cardiovascular disease. We examined the relationship between ECP, carotid plaque, and incidence of stroke in a prospective population-based cohort. The subjects participated in the Malmö Diet and Cancer Study between 1991 and 1994. A total of 4706 subjects with no history of stroke were included (40% men mean age, 57.5 years). Carotid plaque was determined by B-mode ultrasound of the right carotid artery. Incidence of stroke was followed up during a mean period of 16.5 years in relation to plasma ECP levels. Subjects in the third tertile (versus first tertile) of ECP tended to have higher prevalence of carotid plaque (odds ratio: 1.18 95% confidence interval: 1.003–1.39 P =0.044 after multivariate adjustments). A total of 258 subjects were diagnosed with ischemic stroke (IS) during follow-up. ECP was associated with increased incidence of IS after risk factor adjustment (hazard ratio, 1.57 95% confidence interval: 1.13–2.18 for third versus first tertile P =0.007). High ECP was associated with increased risk of IS in subjects with carotid plaque. The risk factor–adjusted hazard ratio for IS was 1.86 (95% confidence interval: 1.32–2.63) in subjects with carotid plaque and ECP in the top tertile, compared with those without plaque and ECP in the first or second tertiles. High ECP is associated with increased incidence of IS. The association between ECP and IS was also present in the subgroup with carotid plaque.
Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population
Publisher: Oxford University Press (OUP)
Date: 20-10-2017
Genetic variation at 16q24.2 is associated with small vessel stroke
Publisher: Wiley
Date: 03-2017
DOI: 10.1002/ANA.24840
Biological, clinical and population relevance of 95 loci for blood lipids
Publisher: Springer Science and Business Media LLC
Date: 08-2010
DOI: 10.1038/NATURE09270
Cardiovascular Risk Factors Associated With Venous Thromboembolism
Publisher: American Medical Association (AMA)
Date: 02-2019
Trans-ethnic association study of blood pressure determinants in over 750,000 individuals
Publisher: Springer Science and Business Media LLC
Date: 21-12-2018
Author Correction: Evaluating drug targets through human loss-of-function genetic variation (Nature, (2020), 581, 7809, (459-464), 10.1038/s41586-020-2267-z)
Publisher: Springer Science and Business Media LLC
Date: 03-02-2021
DOI: 10.1038/S41586-020-03177-5
Abstract: A Correction to this paper has been published: 0.1038/s41586-020-03177-5
Author Correction: Transcript expression-aware annotation improves rare variant interpretation
Publisher: Springer Science and Business Media LLC
Date: 03-02-2021
DOI: 10.1038/S41586-020-03175-7
Abstract: A Correction to this paper has been published: 0.1038/s41586-020-03175-7
Lack of association between genetic variations in the KALRN region and ischemic stroke
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.CLINBIOCHEM.2011.05.025
Abstract: To investigate whether KALRN gene variation is associated with ischemic stroke (IS). Associations to overall IS and IS subtypes were investigated in SAHLSIS, which comprises 844 patients with IS and 668 controls. Associations between KALRN SNPs and overall IS and cardioembolic stroke were detected. Associations for overall IS were investigated in two additional Swedish s les, but could not be replicated. KALRN gene variation is not associated with overall IS.
Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
Publisher: Elsevier BV
Date: 06-2016
Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study
Publisher: Elsevier BV
Date: 02-2016
The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3667
Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility
Publisher: Springer Science and Business Media LLC
Date: 09-02-2014
DOI: 10.1038/NG.2897
Genetic studies of body mass index yield new insights for obesity biology
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
New genetic loci link adipose and insulin biology to body fat distribution
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
Abstract: To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European in iduals and exome sequencing of 12,940 in iduals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1–5%) non-coding variants in the whole-genome sequenced in iduals and 99.7% of low-frequency coding variants in the whole-exome sequenced in iduals. Each variant was tested for association with T2D in the sequenced in iduals, and, to increase power, most were tested in larger numbers of in iduals ( % of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
Multiple Associated Variants Increase the Heritability Explained for Plasma Lipids and Coronary Artery Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
DOI: 10.1161/CIRCGENETICS.113.000420
Abstract: Plasma lipid levels as well as coronary artery disease (CAD) have been shown to be highly heritable with estimates ranging from 40% to 60%. However, top variants detected by large-scale genome-wide association studies explain only a fraction of the total variance in plasma lipid phenotypes and CAD. We performed a conditional and joint association analysis using summary-level statistics from 2 large genome-wide association meta-analyses: the Global Lipids Genetics Consortium (GLGC) study, and the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study. There were 100 184 in iduals from 46 GLGC studies for plasma lipids, and 22 233 cases and 64 762 controls from 14 studies for CAD. We detected several loci where multiple independent single-nucleotide polymorphisms were associated with lipid traits within a locus (12 out of 33 loci for high-density lipoprotein cholesterol, 10 of 35 loci for low-density lipoprotein cholesterol, 13 of 44 loci for total cholesterol, and 8 of 28 loci for triglycerides), reaching genome-wide significance ( P ×10 −8 ), nearly doubling the heritability explained by genome-wide association studies (from 3.6 to 7.6% for high-density lipoprotein cholesterol, from 5.0 to 8.8% for low-density lipoprotein cholesterol, from 5.5 to 8.8% for total cholesterol, and from 5.7 to 8.5% for triglycerides). Multiple single-nucleotide polymorphisms were also associated with CAD (3 of 15 loci an increase from 9.6% to 11.4% of heritability explained). These results demonstrate that a portion of the missing heritability for lipid traits and CAD can be explained by multiple variants at each locus.
Transcript expression-aware annotation improves rare variant interpretation
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41586-020-2329-2
Abstract: The acceleration of DNA sequencing in s les from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable ex le of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy in iduals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD) 1 , we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the ‘proportion expressed across transcripts’, which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue s les from the Genotype Tissue Expression (GTEx) project 2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies.
Related Organisations
Lund University Medical Faculty Foundation
Location: No location found
Related Funding Activities
No related grants have been discovered for Olle Melander.