Mendelian randomization study of whole blood viscosity and cardiovascular diseases

AIMS: Association between whole blood viscosity (WBV) and an increased risk of cardiovascular disease (CVD) has been reported. However, the causal relationship between WBV and CVD remains not thoroughly investigated. The aim of this study was to investigate the causal relation between WBV and CVD.METHODS: Two-sample Mendelian randomization (MR) was employed, with inverse variance weighting (IVW) as the primary method, to investigate the casual relationship between WBV and CVD. The calculated WBV and medical records of 378,210 individuals participating in the UK Biobank study were divided into halves and analyzed.RESULTS: The means of calculated WBVs were 16.9 (standard deviation: 0.8) and 55.1 (standard deviation: 17.2) for high shear rate (HSR) and low shear rate (LSR), respectively. 37,859 (10.0%) major cardiovascular events (MACE) consisted of 23,894 (6.3%) cases of myocardial infarction (MI), 9,245 (2.4%) cases of ischemic stroke, 10,377 (2.7%) cases of revascularization, and 5,703 (1.5%) cases of coronary heart disease-related death. In the MR analysis, no evidence was found indicating a causal effect of WBV on MACE (IVW p-value for HSR = 0.81, IVW p-value for LSR = 0.47), MI (0.92, 0.83), ischemic stroke (0.52, 0.74), revascularization (0.71, 0.54), and coronary heart disease-related death (0.83, 0.70). The lack of sufficient evidence for causality persisted in other MR methods, including weighted median and MR-egger.CONCLUSIONS: The Mendelian randomization analysis conducted in this study does not support a causal relationship between calculated WBV and CVD.</p

Evidence for sex-specific genetic architectures across a spectrum of human complex traits

BACKGROUND: Sex differences are a common feature of human traits; however, the role sex determination plays in human genetic variation remains unclear. The presence of gene-by-sex (GxS) interactions implies that trait genetic architecture differs between men and women. Here, we show that GxS interactions and genetic heterogeneity among sexes are small but common features of a range of high-level complex traits. RESULTS: We analyzed 19 complex traits measured in 54,040 unrelated men and 59,820 unrelated women from the UK Biobank cohort to estimate autosomal genetic correlations and heritability differences between men and women. For 13 of the 19 traits examined, there is evidence that the trait measured is genetically different between males and females. We find that estimates of genetic correlations, based on ~114,000 unrelated individuals and ~19,000 related individuals from the same cohort, are largely consistent. Genetic predictors using a sex-specific model that incorporated GxS interactions led to a relative improvement of up to 4 % (mean 1.4 % across all relevant phenotypes) over those provided by a sex-agnostic model. This further supports the hypothesis of the presence of sexual genetic heterogeneity across high-level phenotypes. CONCLUSIONS: The sex-specific environment seems to play a role in changing genotype expression across a range of human complex traits. Further studies of GxS interactions for high-level human traits may shed light on the molecular mechanisms that lead to biological differences between men and women. However, this may be a challenging endeavour due to the likely small effects of the interactions at individual loci. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-016-1025-x) contains supplementary material, which is available to authorized users

Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson's Disease

Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease etiology. However, intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotypes difficult to assay. Assembling large case–control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging. Imputation of such intermediate phenotypes represents a practical alternative in this context. We used a mixed linear model to impute DNA methylation (DNAm) levels of four brain tissues at up to 1826 methylome-wide sites in 6259 patients with Parkinson’s disease and 9452 controls from across five genome-wide association studies (GWAS). Six sites, in two regions, were found to associate with Parkinson’s disease for at least one tissue. While a majority of identified sites were within an established risk region for Parkinson’s disease, suggesting a role of DNAm in mediating previously observed genetic effects at this locus, we also identify an association with four CpG sites in chromosome 16p11.2. Direct measures of DNAm in the substantia nigra of 39 cases and 13 control samples were used to independently replicate these four associations. Only the association at cg10917602 replicated with a concordant direction of effect (P = 0.02). cg10917602 is 87 kb away from the closest reported GWAS hit. The employed imputation methodology implies that variation of DNAm levels at cg10917602 is predictive for Parkinson’s disease risk, suggesting a possible causal role for methylation at this locus. More generally this study demonstrates the feasibility of identifying predictive epigenetic markers of disease risk from readily available data sets

The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease

Background and Aims: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn’s disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C→T), and OCTN2 variant (SLC22A5 −207G→C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D′, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required. </p