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1.  A blood pressure genetic risk score is a significant predictor of incident cardiovascular events in 32,669 individuals 
Hypertension  2013;61(5):987-994.
Recent genome-wide association studies (GWASs) have identified genetic variants associated with blood pressure (BP). We investigated whether genetic risk scores (GRSs) constructed of these variants would predict incident cardiovascular disease (CVD) events. We genotyped 32 common single nucleotide polymorphisms (SNPs) in several Finnish cohorts, with up to 32,669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2,295 incident CVD events occurred. We created GRSs separately for systolic (SBP) and diastolic BP (DBP) by multiplying the risk allele count of each SNP by the effect size estimated in published GWASs. We performed Cox regression analyses with and without adjustment for clinical factors including BP at baseline in each cohort. The results were combined by inverse variance-weighted fixed-effects meta-analysis. The GRSs were strongly associated with SBP and DBP and baseline hypertension (all p<10−62). Hazard ratios comparing the highest quintiles of SBP and DBP genetic risk scores with the lowest quintiles after adjustment for age, age squared and sex, were 1.25 (1.07–1.46, p = 0.006) and 1.23 (1.05–1.43, p = 0.01), respectively, for incident coronary heart disease; 1.24 (1.01–1.53, p = 0.04) and 1.35 (1.09–1.66, p = 0.005) for incident stroke; and 1.23 (1.08–1.40, p = 2×10−6) and 1.26 (1.11–1.44, p = 5×10−4) for composite CVD. In conclusion, BP findings from GWASs are strongly replicated. GRSs comprised of bona fide BP SNPs predicted cardiovascular disease risk, consistent with a life-long effect on BP of these variants collectively.
PMCID: PMC3648219  PMID: 23509078
Hypertension; blood pressure; genetics; cardiovascular disease; prospective cohort study; genetic risk score
2.  Systematic identification of trans-eQTLs as putative drivers of known disease associations 
Nature genetics  2013;45(10):1238-1243.
Identifying the downstream effects of disease-associated single nucleotide polymorphisms (SNPs) is challenging: the causal gene is often unknown or it is unclear how the SNP affects the causal gene, making it difficult to design experiments that reveal functional consequences. To help overcome this problem, we performed the largest expression quantitative trait locus (eQTL) meta-analysis so far reported in non-transformed peripheral blood samples of 5,311 individuals, with replication in 2,775 individuals. We identified and replicated trans-eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Although we did not study specific patient cohorts, we identified trait-associated SNPs that affect multiple trans-genes that are known to be markedly altered in patients: for example, systemic lupus erythematosus (SLE) SNP rs49170141 altered C1QB and five type 1 interferon response genes, both hallmarks of SLE2-4. Subsequent ChIP-seq data analysis on these trans-genes implicated transcription factor IKZF1 as the causal gene at this locus, with DeepSAGE RNA-sequencing revealing that rs4917014 strongly alters 3’ UTR levels of IKZF1. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
PMCID: PMC3991562  PMID: 24013639
3.  Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders 
Nature neuroscience  2013;16(9):1228-1237.
Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We show here that the enrichment of a rare Chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enables the detection of association between TOP3β and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase is a component of cytosolic messenger ribonucleoproteins (mRNPs) and is catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome (FXS). Thus, we uncover a novel role for TOP3β in mRNA metabolism and provide several lines of evidence implicating it in neurodevelopmental disorders.
PMCID: PMC3986889  PMID: 23912948
4.  Assessing multivariate gene-metabolome associations with rare variants using Bayesian reduced rank regression 
Bioinformatics  2014;30(14):2026-2034.
Motivation: A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype–phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals.
Results: We propose a new statistical approach based on Bayesian reduced rank regression to assess the impact of multiple SNPs on a high-dimensional phenotype. Because of the method’s ability to combine information over multiple SNPs and phenotypes, it is particularly suitable for detecting associations involving rare variants. We demonstrate the potential of our method and compare it with alternatives using the Northern Finland Birth Cohort with 4702 individuals, for whom genome-wide SNP data along with lipoprotein profiles comprising 74 traits are available. We discovered two genes (XRCC4 and MTHFD2L) without previously reported associations, which replicated in a combined analysis of two additional cohorts: 2390 individuals from the Cardiovascular Risk in Young Finns study and 3659 individuals from the FINRISK study.
Availability and implementation: R-code freely available for download at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC4080737  PMID: 24665129
5.  Comparison of Three Troponins as Predictors of Future Cardiovascular Events – Prospective Results from the FINRISK and BiomaCaRE Studies 
PLoS ONE  2014;9(3):e90063.
Importance and Objective
Besides their role in diagnosis of acute myocardial infarction (MI), troponins may be powerful biomarkers for risk stratification in the general population. The objective of our study was to compare the performance of three troponin assays in cardiovascular disease (CVD) risk prediction in a population-based cohort without a history of CVD events.
Design, Setting and Participants
Troponin I concentrations were measured using a contemporary-sensitivity, high-sensitivity, and super-sensitivity assay in 7,899 participants of the general-population based FINRISK 1997 cohort. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for over-optimism.
Main Outcome
As outcome measures we used CVD, MI, ischemic stroke, heart failure (HF), and major adverse cardiac events (MACE). During the follow-up of 14 years 1,074 incident MACE were observed.
Values above the lower limit of detection were observed in 26.4%, 81.5% and 93.9% for the contemporary-sensitivity, high-sensitivity and super-sensitivity assay, respectively. We observed significant associations of troponin concentrations with the risk of future CVD events and the results tended to become stronger with increasing assay sensitivity. For the super-sensitivity assay the multivariate adjusted hazard ratios (per one standard deviation increase) for different outcomes were: MI 1.24 [95% CI 1.11–1.39], stroke 1.14 [1.01–1.28], CVD 1.15 [1.07–1.24], HF 1.28 [1.18–1.39], and MACE 1.18 [1.11–1.25]. In subjects with intermediate risk, we found an improvement of net reclassification for HF (10.2%, p<0.001), and MACE (5.1%, p<0.001).
Using a super-sensitivity assay, cardiac troponin was detectable in almost all healthy individuals. Its concentration improved risk prediction and reclassification for cardiovascular endpoints.
PMCID: PMC3942371  PMID: 24594734
6.  Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons 
PLoS Medicine  2014;11(2):e1001606.
In this study, Würtz and colleagues conducted high-throughput profiling of blood specimens in two large population-based cohorts in order to identify biomarkers for all-cause mortality and enhance risk prediction. The authors found that biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. However, further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers to guide screening and prevention.
Please see later in the article for the Editors' Summary
Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts.
Methods and Findings
106 candidate biomarkers were quantified by nuclear magnetic resonance spectroscopy of non-fasting plasma samples from a random subset of the Estonian Biobank (n = 9,842; age range 18–103 y; 508 deaths during a median of 5.4 y of follow-up). Biomarkers for all-cause mortality were examined using stepwise proportional hazards models. Significant biomarkers were validated and incremental predictive utility assessed in a population-based cohort from Finland (n = 7,503; 176 deaths during 5 y of follow-up). Four circulating biomarkers predicted the risk of all-cause mortality among participants from the Estonian Biobank after adjusting for conventional risk factors: alpha-1-acid glycoprotein (hazard ratio [HR] 1.67 per 1–standard deviation increment, 95% CI 1.53–1.82, p = 5×10−31), albumin (HR 0.70, 95% CI 0.65–0.76, p = 2×10−18), very-low-density lipoprotein particle size (HR 0.69, 95% CI 0.62–0.77, p = 3×10−12), and citrate (HR 1.33, 95% CI 1.21–1.45, p = 5×10−10). All four biomarkers were predictive of cardiovascular mortality, as well as death from cancer and other nonvascular diseases. One in five participants in the Estonian Biobank cohort with a biomarker summary score within the highest percentile died during the first year of follow-up, indicating prominent systemic reflections of frailty. The biomarker associations all replicated in the Finnish validation cohort. Including the four biomarkers in a risk prediction score improved risk assessment for 5-y mortality (increase in C-statistics 0.031, p = 0.01; continuous reclassification improvement 26.3%, p = 0.001).
Biomarker associations with cardiovascular, nonvascular, and cancer mortality suggest novel systemic connectivities across seemingly disparate morbidities. The biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. Further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers for guiding screening and prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
A biomarker is a biological molecule found in blood, body fluids, or tissues that may signal an abnormal process, a condition, or a disease. The level of a particular biomarker may indicate a patient's risk of disease, or likely response to a treatment. For example, cholesterol levels are measured to assess the risk of heart disease. Most current biomarkers are used to test an individual's risk of developing a specific condition. There are none that accurately assess whether a person is at risk of ill health generally, or likely to die soon from a disease. Early and accurate identification of people who appear healthy but in fact have an underlying serious illness would provide valuable opportunities for preventative treatment.
While most tests measure the levels of a specific biomarker, there are some technologies that allow blood samples to be screened for a wide range of biomarkers. These include nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. These tools have the potential to be used to screen the general population for a range of different biomarkers.
Why Was This Study Done?
Identifying new biomarkers that provide insight into the risk of death from all causes could be an important step in linking different diseases and assessing patient risk. The authors in this study screened patient samples using NMR spectroscopy for biomarkers that accurately predict the risk of death particularly amongst the general population, rather than amongst people already known to be ill.
What Did the Researchers Do and Find?
The researchers studied two large groups of people, one in Estonia and one in Finland. Both countries have set up health registries that collect and store blood samples and health records over many years. The registries include large numbers of people who are representative of the wider population.
The researchers first tested blood samples from a representative subset of the Estonian group, testing 9,842 samples in total. They looked at 106 different biomarkers in each sample using NMR spectroscopy. They also looked at the health records of this group and found that 508 people died during the follow-up period after the blood sample was taken, the majority from heart disease, cancer, and other diseases. Using statistical analysis, they looked for any links between the levels of different biomarkers in the blood and people's short-term risk of dying. They found that the levels of four biomarkers—plasma albumin, alpha-1-acid glycoprotein, very-low-density lipoprotein (VLDL) particle size, and citrate—appeared to accurately predict short-term risk of death. They repeated this study with the Finnish group, this time with 7,503 individuals (176 of whom died during the five-year follow-up period after giving a blood sample) and found similar results.
The researchers carried out further statistical analyses to take into account other known factors that might have contributed to the risk of life-threatening illness. These included factors such as age, weight, tobacco and alcohol use, cholesterol levels, and pre-existing illness, such as diabetes and cancer. The association between the four biomarkers and short-term risk of death remained the same even when controlling for these other factors.
The analysis also showed that combining the test results for all four biomarkers, to produce a biomarker score, provided a more accurate measure of risk than any of the biomarkers individually. This biomarker score also proved to be the strongest predictor of short-term risk of dying in the Estonian group. Individuals with a biomarker score in the top 20% had a risk of dying within five years that was 19 times greater than that of individuals with a score in the bottom 20% (288 versus 15 deaths).
What Do These Findings Mean?
This study suggests that there are four biomarkers in the blood—alpha-1-acid glycoprotein, albumin, VLDL particle size, and citrate—that can be measured by NMR spectroscopy to assess whether otherwise healthy people are at short-term risk of dying from heart disease, cancer, and other illnesses. However, further validation of these findings is still required, and additional studies should examine the biomarker specificity and associations in settings closer to clinical practice. The combined biomarker score appears to be a more accurate predictor of risk than tests for more commonly known risk factors. Identifying individuals who are at high risk using these biomarkers might help to target preventative medical treatments to those with the greatest need.
However, there are several limitations to this study. As an observational study, it provides evidence of only a correlation between a biomarker score and ill health. It does not identify any underlying causes. Other factors, not detectable by NMR spectroscopy, might be the true cause of serious health problems and would provide a more accurate assessment of risk. Nor does this study identify what kinds of treatment might prove successful in reducing the risks. Therefore, more research is needed to determine whether testing for these biomarkers would provide any clinical benefit.
There were also some technical limitations to the study. NMR spectroscopy does not detect as many biomarkers as mass spectrometry, which might therefore identify further biomarkers for a more accurate risk assessment. In addition, because both study groups were northern European, it is not yet known whether the results would be the same in other ethnic groups or populations with different lifestyles.
In spite of these limitations, the fact that the same four biomarkers are associated with a short-term risk of death from a variety of diseases does suggest that similar underlying mechanisms are taking place. This observation points to some potentially valuable areas of research to understand precisely what's contributing to the increased risk.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute of Environmental Health Sciences has information on biomarkers
The US Food and Drug Administration has a Biomarker Qualification Program to help researchers in identifying and evaluating new biomarkers
Further information on the Estonian Biobank is available
The Computational Medicine Research Team of the University of Oulu and the University of Bristol have a webpage that provides further information on high-throughput biomarker profiling by NMR spectroscopy
PMCID: PMC3934819  PMID: 24586121
7.  Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation 
PLoS Genetics  2014;10(2):e1004127.
The X chromosome (chrX) represents one potential source for the “missing heritability” for complex phenotypes, which thus far has remained underanalyzed in genome-wide association studies (GWAS). Here we demonstrate the benefits of including chrX in GWAS by assessing the contribution of 404,862 chrX SNPs to levels of twelve commonly studied cardiometabolic and anthropometric traits in 19,697 Finnish and Swedish individuals with replication data on 5,032 additional Finns. By using a linear mixed model, we estimate that on average 2.6% of the additive genetic variance in these twelve traits is attributable to chrX, this being in proportion to the number of SNPs in the chromosome. In a chrX-wide association analysis, we identify three novel loci: two for height (rs182838724 near FGF16/ATRX/MAGT1, joint P-value = 2.71×10−9, and rs1751138 near ITM2A, P-value = 3.03×10−10) and one for fasting insulin (rs139163435 in Xq23, P-value = 5.18×10−9). Further, we find that effect sizes for variants near ITM2A, a gene implicated in cartilage development, show evidence for a lack of dosage compensation. This observation is further supported by a sex-difference in ITM2A expression in whole blood (P-value = 0.00251), and is also in agreement with a previous report showing ITM2A escapes from X chromosome inactivation (XCI) in the majority of women. Hence, our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height. In conclusion, our study provides a clear motivation for including chrX in large-scale genetic studies of complex diseases and traits.
Author Summary
The X chromosome (chrX) analyses have often been neglected in large-scale genome-wide association studies. Given that chrX contains a considerable proportion of DNA, we wanted to examine how the variation in the chromosome contributes to commonly studied phenotypes. To this end, we studied the associations of over 400,000 chrX variants with twelve complex phenotypes, such as height, in almost 25,000 Northern European individuals. Demonstrating the value of assessing chrX associations, we found that as a whole the variation in the chromosome influences the levels of many of these phenotypes and further identified three new genomic regions where the variants associate with height or fasting insulin levels. In one of these three associated regions, the region near ITM2A, we observed that there is a sex difference in the genetic effects on height in a manner consistent with a lack of dosage compensation in this locus. Further supporting this observation, ITM2A has been shown to be among those chrX genes where the X chromosome inactivation is incomplete. Identifying phenotype associations in regions like this where chrX allele dosages are not balanced between men and women can be particularly valuable in helping us to understand why some characteristics differ between sexes.
PMCID: PMC3916240  PMID: 24516404
8.  The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies 
Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies.
Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18–80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease.
Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes.
Through a rigorous harmonization process, the BioSHaRE-EU consortium was able to compare key characteristics defining the metabolically healthy obese phenotype across ten cohort studies. There is considerable variability in the prevalence of healthy obesity across the different European populations studied, even when unified criteria were used to classify this phenotype.
PMCID: PMC3923238  PMID: 24484869
Harmonization; Obesity; Metabolic syndrome; Cardiovascular disease; Metabolically healthy
9.  High Risk Population Isolate Reveals Low Frequency Variants Predisposing to Intracranial Aneurysms 
PLoS Genetics  2014;10(1):e1004134.
3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.
Author Summary
Genome-wide association studies (GWAS) have been extensively used to identify common genetic variants associated with complex diseases. As common genetic variants have explained only a small fraction of the heritability of most complex diseases, there is a growing interest in the role of how low frequency and rare variants contribute to the susceptibility. Low frequency variants are more often specific to populations of distinct ancestries. Saccular intracranial aneurysms (sIA) are balloon-like dilatations in the arteries on the surface of the brain. The rupture of sIA causes life-threatening intracranial bleeding. sIA is a complex disease, which is known to sometimes run in families. Here, we utilize the recent advancements in knowledge of genetic variation in different populations to examine the role of low-frequency variants in sIA disease in the isolated population of Finland where sIA related strokes are more common than in most other populations. By studying >8000 Finns we identify four low-frequency variants associated with the sIA disease. We also show that the association of two of the variants are seen in other European populations as well. Our findings demonstrate that multiple study designs are needed to uncover more comprehensively their genetic background, including population isolates.
PMCID: PMC3907358  PMID: 24497844
10.  Cause-specific mortality of 1-year survivors of subarachnoid hemorrhage 
Neurology  2013;80(5):481-486.
To assess long-term, cause-specific mortality rates and rate ratios of the patients alive at 1 year after subarachnoid hemorrhage (SAH).
The population-based, prospective, cohort study with a nested case-control design consisted of 64,349 persons (aged 25–74 years at enrollment) who participated in the National FINRISK Study between 1972 and 2007. Four hundred thirty-seven SAH cases, 233 one-year SAH survivors, and their matched intrinsic controls were identified and followed up until the end of 2009 through the nationwide Finnish Causes of Death Register. All-cause mortality rates and rate ratios of the 1-year SAH survivors and controls were the main outcome measures.
Eighty-eight (37.8%) of 233 one-year SAH survivors died during the total follow-up time of 2,487 person-years (median 8.6 years, range 0.1–35.8 years). The 1-year SAH survivors had a hazard ratio of 1.96 (95% confidence interval 1.57–2.47) for death compared with the matched general population with 10 controls for each SAH survivor. One-year SAH survivors had up to 31 additional deaths per 1,000 person-years compared with controls with minimal cerebrovascular risk factors. The higher long-term risk of death among SAH survivors was attributed solely to cerebrovascular diseases, and most important modifiable risk factors for death were smoking, high systolic blood pressure (≥159 mm Hg), and high cholesterol levels (≥7.07 mmol/L).
One-year SAH survivors have excess mortality, which is attributed to an exceptional risk of deadly cerebrovascular events. Aggressive post-SAH cerebrovascular risk factor intervention strategies are highly warranted.
PMCID: PMC3590048  PMID: 23303843
11.  Ischaemic stroke is associated with the ABO locus: the Euroclot study 
Annals of neurology  2013;73(1):16-31.
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n=2,100 Stage 1) were examined in ischemic stroke (n=4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases 55,000 controls) was used for replication (Stage 3).
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. Most striking associations included SNP rs5985 with factor XIII activity (p=2.6×10-186), rs10665 with FVII (p = 2.4×10-47) and rs505922 in the ABO gene with both von Willebrand Factor (vWF p=4.7×10-57) and factor VIII (p=1.2×10-36). In Stage 2, the 23 independent SNPs were examined in stroke cases/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=0.066 (0.02) p = 0.001, a finding specific to large vessel and cardioembolic stroke (p = 0.001 and p = <0.001 respectively) but not seen with small vessel stroke (p=0.811).
ABO gene variants are associated with large vessel and cardioembolic stroke but not small vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
PMCID: PMC3582024  PMID: 23381943
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
12.  Assessing Risk Prediction Models Using Individual Participant Data From Multiple Studies 
Pennells, Lisa | Kaptoge, Stephen | White, Ian R. | Thompson, Simon G. | Wood, Angela M. | Tipping, Robert W. | Folsom, Aaron R. | Couper, David J. | Ballantyne, Christie M. | Coresh, Josef | Goya Wannamethee, S. | Morris, Richard W. | Kiechl, Stefan | Willeit, Johann | Willeit, Peter | Schett, Georg | Ebrahim, Shah | Lawlor, Debbie A. | Yarnell, John W. | Gallacher, John | Cushman, Mary | Psaty, Bruce M. | Tracy, Russ | Tybjærg-Hansen, Anne | Price, Jackie F. | Lee, Amanda J. | McLachlan, Stela | Khaw, Kay-Tee | Wareham, Nicholas J. | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Jansson, Jan-Håkan | Wennberg, Patrik | Salomaa, Veikko | Harald, Kennet | Jousilahti, Pekka | Vartiainen, Erkki | Woodward, Mark | D'Agostino, Ralph B. | Bladbjerg, Else-Marie | Jørgensen, Torben | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Dekker, Jacqueline M. | Nijpels, Giel | Stehouwer, Coen D. A. | Kauhanen, Jussi | Salonen, Jukka T. | Meade, Tom W. | Cooper, Jackie A. | Cushman, Mary | Folsom, Aaron R. | Psaty, Bruce M. | Shea, Steven | Döring, Angela | Kuller, Lewis H. | Grandits, Greg | Gillum, Richard F. | Mussolino, Michael | Rimm, Eric B. | Hankinson, Sue E. | Manson, JoAnn E. | Pai, Jennifer K. | Kirkland, Susan | Shaffer, Jonathan A. | Shimbo, Daichi | Bakker, Stephan J. L. | Gansevoort, Ron T. | Hillege, Hans L. | Amouyel, Philippe | Arveiler, Dominique | Evans, Alun | Ferrières, Jean | Sattar, Naveed | Westendorp, Rudi G. | Buckley, Brendan M. | Cantin, Bernard | Lamarche, Benoît | Barrett-Connor, Elizabeth | Wingard, Deborah L. | Bettencourt, Richele | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Kavousi, Maryam | Witteman, Jacqueline C. | Hofman, Albert | Franco, Oscar H. | Howard, Barbara V. | Zhang, Ying | Best, Lyle | Umans, Jason G. | Onat, Altan | Sundström, Johan | Michael Gaziano, J. | Stampfer, Meir | Ridker, Paul M. | Michael Gaziano, J. | Ridker, Paul M. | Marmot, Michael | Clarke, Robert | Collins, Rory | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimäki, Mika | Ridker, Paul M. | Buring, Julie | Cook, Nancy | Ford, Ian | Shepherd, James | Cobbe, Stuart M. | Robertson, Michele | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S. | Angelantonio, Emanuele Di | Gao, Pei | Haycock, Philip | Kaptoge, Stephen | Pennells, Lisa | Thompson, Simon G. | Walker, Matthew | Watson, Sarah | White, Ian R. | Wood, Angela M. | Wormser, David | Danesh, John
American Journal of Epidemiology  2013;179(5):621-632.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
13.  Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies 
PLoS ONE  2013;8(12):e83101.
Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.
PMCID: PMC3858365  PMID: 24340086
14.  Outcome up to one year following different reperfusion strategies in acute ST-segment elevation myocardial infarction: The Helsinki-Uusimaa Hospital District registry of ST-Elevation Acute Myocardial Infarction (HUS-STEMI) 
Current guidelines prefer primary percutaneous coronary intervention (pPCI) over fibrinolysis in the treatment of acute ST-elevation myocardial infarction (STEMI). Pre-hospital fibrinolysis followed by early invasive evaluation is an alternative that we have used in patients presenting within three hours of symptom onset. We made a survey of patients suffering an acute STEMI over one year to assess mortality and adverse events following either pPCI or fibrinolysis.
Methods and results:
Of the 448 consecutive STEMI patients, 194 were treated with pPCI and 176 underwent fibrinolysis; 78 patients received no reperfusion treatment within 12 hours (NRT group). The median TIMI risk scores were 4.0, 3.0 and 4.0 in the pPCI, fibrinolysis and NRT groups, respectively (p<0.001). Mortality at one year was 14.4% following pPCI, 5.1% following fibrinolysis and 12.8% in the NRT group (p=0.011 across all groups and p=0.003 between pPCI and fibrinolysis, adjusted for differences in risk factors). The one-year composite of cardiovascular death, stroke, reinfarction and new revascularization was 20.1%, 18.2% and 26.9% for the pPCI, fibrinolysis and NRT groups, respectively (p=NS). In patients presenting within three hours of symptom onset, one-year mortality was 3.7% in the fibrinolysis group (n=163) and 15.3% in the pPCI group (n=118) (adjusted p =0.001), while the composite of adverse events was 16.6% in the former group and 19.5% in the latter (p=NS).
Pre-hospital fibrinolysis followed by routine early invasive evaluation provides an excellent reperfusion strategy for low-risk STEMI patients presenting early after symptom onset.
PMCID: PMC3821832  PMID: 24338296
Myocardial infarction; primary angioplasty; fibrinolysis
15.  Partial Sleep Restriction Activates Immune Response-Related Gene Expression Pathways: Experimental and Epidemiological Studies in Humans 
PLoS ONE  2013;8(10):e77184.
Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling (P<0.005). Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.
PMCID: PMC3806729  PMID: 24194869
16.  Prevalence of arrhythmia-associated gene mutations and risk of sudden cardiac death in the Finnish population 
Annals of medicine  2013;45(4):328-335.
Sudden cardiac death (SCD) remains a major cause of death in Western Countries. It has a heritable component, but previous molecular studies have mainly focused on common genetic variants. We studied the prevalence, clinical phenotypes, and risk of SCD presented by ten rare mutations previously associated with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, or catecholaminergic polymorphic ventricular tachycardia.
The occurrence of ten arrhythmia-associated mutations was determined in four large prospective population cohorts (FINRISK 1992, 1997, 2002, and Health 2000, n = 28,465) and two series of forensic autopsies (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 825). Follow-up data was collected from national registries.
The ten mutations showed a combined prevalence of 79 per 10,000 individuals in Finland and six of them showed remarkable geographic clustering. Of a total of 715 SCD cases, seven (1.0%) carried one of the ten mutations assayed: three carried KCNH2 R176W, one KCNH2 L552S, two PKP2 Q59L, and one RYR2 R3570W.
Arrhythmia-associated mutations are prevalent in the general Finnish population but do not seem to present a major risk factor for SCD, at least during a mean of 10-year follow-up of a random adult population sample.
PMCID: PMC3778376  PMID: 23651034
Arrhythmia; Genetic epidemiology; Genetics; Mutation; Sudden cardiac death
17.  Risk Factors and Their Combined Effects on the Incidence Rate of Subarachnoid Hemorrhage – A Population-Based Cohort Study 
PLoS ONE  2013;8(9):e73760.
Prospective studies on the risk factors for subarachnoid hemorrhage (SAH) are limited. Moreover, the effect of risk factors on the incidence rates of SAH is not well known about.
In this study, we aimed to identify risk factors for SAH and characterize subgroups in a population with a high incidence of SAH.
After recording multiple potential risk factors for SAH at the time of enrolment, first ever SAH events between 1972 and 2009 were recorded through the nationwide Causes of Death Register and Hospital Discharge Register for the population-based cohort of 64 349 participants, who participated in the National FINRISK Study between 1972 and 2007 in Finland.
During the follow-up time of 1.26 million person-years (median 17.9 years, range 0 to 37.9 years), 437 persons experienced fatal or non-fatal SAH. Crude SAH incidence was 34.8 (95% confidence interval: 31.7–38.2) per 100 000 person-years among ≥25-year-old persons. Female sex, high blood pressure values and current smoking were confirmed as risk factors for SAH. Previous myocardial infarction, history of premature stroke (any kind) in mother and elevated cholesterol levels in men were identified as new risk factors for SAH. Depending on the combination of risk factors, SAH incidence varied between 8 and 171 per 100 000 person-years.
New and previously reported risk factors appear to have a much stronger association with the incidence of SAH than is ordinarily seen in cardiovascular diseases. Risk factor assessments may facilitate the identification of high-risk persons who should be the focus of preventive interventions.
PMCID: PMC3767622  PMID: 24040058
T-peak to T-end (TPE) interval on the electrocardiogram (ECG) is a measure of myocardial dispersion of repolarization and is associated with increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown.
We sought to identify common genetic variants that affect the TPE-interval duration in the general population.
We performed a genome-wide association study on 1 870 individuals of Finnish origin participating in the Health 2000 Study. TPE interval was measured from T-peak to T-wave end in leads II, V2 and V5 on resting ECGs and the mean of these TPE intervals was adjusted for age, sex and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3 745 subjects from the Framingham Heart Study.
We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P=1.1×10−10). The association was replicated in the Framingham Heart Study (−1.5 ms, P=1.3×10−4).The overall effect estimate of rs7219669 in the two studies was −1.7 ms (P=5.7×10−14). The common variant rs7219669 maps downstream of KCNJ2 gene, in which rare mutations cause congenital Long- and Short-QT syndromes.
The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.
PMCID: PMC3690340  PMID: 22342860
Electrocardiography; Repolarization; T wave; Epidemiology; Genetics; Polymorphism
19.  Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study 
The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers.
PMCID: PMC3709115  PMID: 23875064
Nicotinic acetylcholine receptors; 15q25.1; alcohol use; smoking behavior; public health; population-based sample; genetic association
20.  Genome-wide association study identifies multiple loci influencing human serum metabolite levels 
Nature genetics  2012;44(3):269-276.
Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.
PMCID: PMC3605033  PMID: 22286219
21.  Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts 
PLoS Medicine  2013;10(2):e1001383.
A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
Methods and Findings
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects.
Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
Please see later in the article for the Editors' Summary
Editors' Summary
Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements.
Why Was This Study Done?
Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations.
What Did the Researchers Do and Find?
The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium.
What Do These Findings Mean?
These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health.
Additional Information
Please access these Web sites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population
The World Health Organization provides information on obesity (in several languages)
The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D
The International Obesity Taskforce provides information about the global obesity epidemic
The US Department of Agriculture's website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish)
MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits
PMCID: PMC3564800  PMID: 23393431
22.  An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia 
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
Methods and Results
First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
PMCID: PMC3562702  PMID: 21597005
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
23.  Genome-wide Association Study for Coronary Artery Calcification with Follow-up in Myocardial Infarction 
Circulation  2011;124(25):2855-2864.
Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.
Methods and Results
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
PMCID: PMC3397173  PMID: 22144573
cardiac computed tomography; coronary artery calcification; coronary atherosclerosis; genome-wide association studies; myocardial infarction
24.  Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure 
Nature genetics  2009;41(3):348-353.
We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure–lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 × 10−70), rs198358 (P = 8 × 10−30) and rs632793 (P = 2 × 10−10), and of plasma B-type natriuretic peptide with rs5068 (P = 3 × 10−12), rs198358 (P = 1 × 10−25) and rs632793 (P = 2 × 10−68). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 × 10−6 and 6 × 10−5, respectively) and diastolic blood pressure (P = 1 × 10−6 and 5 × 10−5), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79–0.92, P = 4 × 10−5; OR = 0.90, 95% CI = 0.85–0.95, P = 2 × 10−4, respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.
PMCID: PMC2664511  PMID: 19219041
25.  Identification of IL6R and chromosome 11q13.5 as risk loci for asthma 
Lancet  2011;378(9795):1006-1014.
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying asthma.
We performed a genome-wide association study (GWAS) in 2,669 physician-diagnosed asthmatics and 4,528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-SNP scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset.
Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR=1.09, combined P=2.4×10−8) in the interleukin-6 receptor gene (IL6R) and rs7130588 (OR=1.09, P=1.8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR = 1.33, P = 7×10−4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-SNP association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that may be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP and BACH2.
The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.
A full list of funding sources appears at the end of the paper.
PMCID: PMC3517659  PMID: 21907864

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