Modelling the genetic aetiology of complex disease: human-mouse conservation of noncoding features and disease-associated loci

Understanding the genetic aetiology of loci associated with a disease is crucial for developing preventative measures and effective treatments. Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, the utility of mouse models is limited in part by evolutionary divergence in transcription regulation for pathways of interest. Here, we summarize the alignment of genomic (exonic and multi-cell regulatory) annotations alongside Mendelian and complex disease-associated variant sites between humans and mice. Our results highlight the importance of understanding evolutionary divergence in transcription regulation when interpreting functional studies using mice as models for human disease variants

MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition

Abstract Background: Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored. Methods: An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue. Findings: We found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways. Interpretation: These data identify a role for miR-196a in regulating human body fat distribution.: This work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

OBJECTIVE: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. RESEARCH DESIGN AND METHODS: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment. RESULTS: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08–1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17–1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs. CONCLUSIONS: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes

Variable strength of forest stand attributes and weather conditions on the questing activity of Ixodes ricinus ticks over years in managed forests

Given the ever-increasing human impact through land use and climate change on the environment, we crucially need to achieve a better understanding of those factors that influence the questing activity of ixodid ticks, a major disease-transmitting vector in temperate forests. We investigated variation in the relative questing nymph densities of Ixodes ricinus in differently managed forest types for three years (2008–2010) in SW Germany by drag sampling. We used a hierarchical Bayesian modeling approach to examine the relative effects of habitat and weather and to consider possible nested structures of habitat and climate forces. The questing activity of nymphs was considerably larger in young forest successional stages of thicket compared with pole wood and timber stages. Questing nymph density increased markedly with milder winter temperatures. Generally, the relative strength of the various environmental forces on questing nymph density differed across years. In particular, winter temperature had a negative effect on tick activity across sites in 2008 in contrast to the overall effect of temperature across years. Our results suggest that forest management practices have important impacts on questing nymph density. Variable weather conditions, however, might override the effects of forest management practices on the fluctuations and dynamics of tick populations and activity over years, in particular, the preceding winter temperatures. Therefore, robust predictions and the detection of possible interactions and nested structures of habitat and climate forces can only be quantified through the collection of long-term data. Such data are particularly important with regard to future scenarios of forest management and climate warming

Clinical predictors of lacunar syndrome not due to lacunar infarction

Background: Lacunar syndrome not due to lacunar infarct is poorly characterised. This single centre, retrospective study was conducted to describe the clinical characteristics of patients with lacunar syndrome not due to lacunar infarct and to identify clinical predictors of this variant of lacunar stroke. Methods: A total of 146 patients with lacunar syndrome not due to lacunar infarction were included in the "Sagrat Cor Hospital of Barcelona Stroke Registry" during a period of 19 years (1986-2004). Data from stroke patients are entered in the stroke registry following a standardized protocol with 161 items regarding demographics, risk factors, clinical features, laboratory and neuroimaging data, complications and outcome. The characteristics of these 146 patients with lacunar syndrome not due to lacunar infarct were compared with those of the 733 patients with lacunar infarction. Results: Lacunar syndrome not due to lacunar infarct accounted for 16.6% (146/879) of all cases of lacunar stroke. Subtypes of lacunar syndromes included pure motor stroke in 63 patients, sensorimotor stroke in 51, pure sensory stroke in 14, atypical lacunar syndrome in 9, ataxic hemiparesis in 5 and dysarthria-clumsy hand in 4. Valvular heart disease, atrial fibrillation, sudden onset, limb weakness and sensory symptoms were significantly more frequent among patients with lacunar syndrome not due to lacunar infarct than in those with lacunar infarction, whereas diabetes was less frequent. In the multivariate analysis, atrial fibrillation (OR = 4.62), sensorimotor stroke (OR = 4.05), limb weakness (OR = 2.09), sudden onset (OR = 2.06) and age (OR = 0.96) were independent predictors of lacunar syndrome not due to lacunar infarct. Conclusions: Although lacunar syndromes are highly suggestive of small deep cerebral infarctions, lacunar syndromes not due to lacunar infarcts are found in 16.6% of cases. The presence of sensorimotor stroke, limb weakness and sudden onset in a patient with atrial fibrillation should alert the clinician to the possibility of a lacunar syndrome not due to a lacunar infarct

Trackways Produced by Lungfish During Terrestrial Locomotion

Some primarily aquatic vertebrates make brief forays onto land, creating traces as they do. A lack of studies on aquatic trackmakers raises the possibility that such traces may be ignored or misidentified in the fossil record. Several terrestrial Actinopterygian and Sarcopterygian species have previously been proposed as possible models for ancestral tetrapod locomotion, despite extant fishes being quite distinct from Devonian fishes, both morphologically and phylogenetically. Although locomotion has been well-studied in some of these taxa, trackway production has not. We recorded terrestrial locomotion of a 35 cm African lungfish (Protopterus annectens; Dipnoi: Sarcopterygii) on compliant sediment. Terrestrial movement in the lungfish is accomplished by planting the head and then pivoting the trunk. Impressions are formed where the head impacts the substrate, while the body and fins produce few traces. The head leaves a series of alternating left-right impressions, where each impact can appear as two separate semi-circular impressions created by the upper and lower jaws, bearing some similarity to fossil traces interpreted as footprints. Further studies of trackways of extant terrestrial fishes are necessary to understand the behavioural repertoire that may be represented in the fossil track record