Wellcome Trust Centre for Human Genetics

About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.

Association of UV radiation with multiple sclerosis prevalence and sex ratio in France

Abstract: Background: French farmers and their families constitute an informative population to study multiple sclerosis (MS) prevalence and related epidemiology. We carried out an ecological study to evaluate the association of MS prevalence and ultraviolet (UV) radiation, a candidate climatologic risk factor. Methods: Mean annual and winter (December–March) UVB irradiation values were systematically compared to MS prevalence rates in corresponding regions of France. UVB data were obtained from the solar radiation database (SoDa) service and prevalence rates from previously published data on 2,667 MS cases registered with the national farmer health insurance system, Mutualite Sociale Agricole (MSA). Pearson correlation was used to examine the relationship of annual and winter UVB values with MS prevalence. Male and female prevalence were also analyzed separately. Linear regression was used to test for interaction of annual and winter UVB with sex in predicting MS prevalence. Results: There was a strong association between MS prevalence and annual mean UVB irradiation (r = −0.80, p < 0.001) and average winter UVB (r = −0.87, p < 0.001). Both female (r = −0.76, p < 0.001) and male (r = −0.46, p = 0.032) prevalence rates were correlated with annual UVB. Regression modeling showed that the effect of UVB on prevalence rates differed by sex; the interaction effect was significant for both annual UVB (p = 0.003) and winter UVB (p = 0.002). Conclusions: The findings suggest that regional UVB radiation is predictive of corresponding MS prevalence rates and supports the hypothesis that sunlight exposure influences MS risk. The evidence also supports a potential role for gender-specific effects of UVB exposure.

Genomic modulators of gene expression in human neutrophils

Abstract: Neutrophils form the most abundant leukocyte subset and are central to many disease processes. Technical challenges in transcriptomic profiling have prohibited genomic approaches to date. Here we map expression quantitative trait loci (eQTL) in peripheral blood CD16+ neutrophils from 101 healthy European adults. We identify cis-eQTL for 3281 neutrophil-expressed genes including many implicated in neutrophil function, with 450 of these not previously observed in myeloid or lymphoid cells. Paired comparison with monocyte eQTL demonstrates nuanced conditioning of genetic regulation of gene expression by cellular context, which relates to cell-type-specific DNA methylation and histone modifications. Neutrophil eQTL are markedly enriched for trait-associated variants particularly autoimmune, allergy and infectious disease. We further demonstrate how eQTL in PADI4 and NOD2 delineate risk variant function in rheumatoid arthritis, leprosy and Crohn's disease. Taken together, these data help advance understanding of the genetics of gene expression, neutrophil biology and immune-related diseases.

Mitochondrial DNA and Y-chromosome variation in the caucasus.

Abstract: We have analyzed mtDNA HVI sequences and Y chromosome haplogroups based on 11 binary markers in 371 individuals, from 11 populations in the Caucasus and the neighbouring countries of Turkey and Iran. Y chromosome haplogroup diversity in the Caucasus was almost as high as in Central Asia and the Near East, and significantly higher than in Europe. More than 27% of the variance in Y-haplogroups can be attributed to differences between populations, whereas mtDNA showed much lower heterogeneity between populations (less then 5%), suggesting a strong influence of patrilocal social structure. Several groups from the highland region of the Caucasus exhibited low diversity and high differentiation for either or both genetic systems, reflecting enhanced genetic drift in these small, isolated populations. Overall, the Caucasus groups showed greater similarity with West Asian than with European groups for both genetic systems, although this similarity was much more pronounced for the Y chromosome than for mtDNA, suggesting that male-mediated migrations from West Asia have influenced the genetic structure of Caucasus populations.

RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport.

Abstract: The critical observation in the pathology of Parkinson's disease (PD) is that neurodegeneration is largely restricted to dopaminergic neurons that develop cytoplasmic inclusions called Lewy bodies. These aggregations contain the protein alpha-synuclein. Furthermore, it is becoming apparent that alpha-synuclein expression levels are a major factor in PD pathogenesis. Patients with additional copies of the alpha-synuclein gene develop PD with a severity proportional to levels of alpha-synuclein overexpression. Similarly, overexpression of alpha-synuclein in in vitro and in vivo models has been shown to be toxic. However, little is known about the effects of reducing alpha-synuclein expression in human neurons. To investigate this, we have developed a system in which levels of alpha-synuclein can be acutely suppressed by using RNA interference (RNAi) in a physiologically relevant human dopaminergic cellular model. By using small interfering RNA (siRNA) molecules targeted to endogenous alpha-synuclein, we achieved 80% protein knockdown. We show that alpha-synuclein knockdown has no effect on cellular survival either under normal growth conditions over 5 days or in the presence of the mitochondrial inhibitor rotenone. Knockdown does, however, confer resistance to the dopamine transporter (DAT)-dependent neurotoxin N-methyl-4-phenylpyridinium (MPP(+)). We then demonstrate for the first time that alpha-synuclein suppression decreases dopamine transport in human cells, reducing the maximal uptake velocity (V(max)) of dopamine and the surface density of its transporter by up to 50%. These results show that RNAi-mediated alpha-synuclein knockdown alters cellular dopamine homeostasis in human cells and may suggest a mechanism for the increased survival in the presence of MPP(+), a toxin used extensively to model Parkinson's disease.

Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes.

Abstract: The aim of this study was to measure the heritability estimates for metabolic traits and the features of the insulin resistance syndrome in families with an increased genetic susceptibility to Type 2 diabetes. A total of 811 non-diabetic relatives from 278 pedigrees of northern European extraction in which there was a sib-pair with Type 2 diabetes were recruited and studied at the six Diabetes UK Warren Type 2 diabetes centres. Heritability estimates were calculated, allowing for key covariates (age, sex, BMI and recruitment centre). Values greater than 0.10 were considered statistically significant in comparison to zero. Fasting glucose concentration and homeostasis model assessment of pancreatic beta cell function (HOMA %B) had the highest heritability estimates of 0.72 and 0.78 respectively. Heritability estimates for the features of the insulin resistance syndrome (BMI, WHR, systolic and diastolic blood pressure, serum lipids and homeostasis model assessment of insulin sensitivity [HOMA %S]) were also high. The heritability estimate for fasting glucose was markedly higher in the present study (0.77 vs 0.21 adjusted for age and sex; p<0.001) than in a comparable study of families from the same background population but with no increased susceptibility to diabetes. However, the estimates for the features of the insulin resistance syndrome were similar in the two studies. In families with a high risk of Type 2 diabetes, the heritability estimates for fasting glucose, pancreatic beta cell function and the features of the insulin resistance syndrome were all high. The higher heritability estimate for pancreatic beta cell function suggests that this resource may be most effective when investigating genetic susceptibility to beta cell dysfunction.