Suchergebnisse

Background: Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. Methods: In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. Findings: We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10-8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10-12for lumbar spine and p=1·9×10-4for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09-1·52, p=0·002) and osteoporosis (OR 1·3, 1·08-1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10-10for lumbar spine and p=3·3×10-8for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01-1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10-6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10-17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08-1·63, p=0·006) and this effect was independent of bone mineral density. Interpretation: Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening. Funding: Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14$^{+}$ monocytes, CD16$^{+}$ neutrophils, and naive CD4$^{+}$ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of $\textit{cis}$-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk. ; This work was predominantly funded by the EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510) and the Canadian Institutes of Health Research (CIHR EP1-120608). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 282510 (BLUEPRINT), the European Molecular Biology Laboratory, the Max Planck society, the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208 and Spanish National Bioinformatics Institute (INB-ISCIII) PT13/0001/0021 co-funded by FEDER ""Una Manera de hacer Europa". D.G. is supported by a "la Caixa"-Severo Ochoa pre-doctoral fellowship, M.F. was supported by the BHF Cambridge Centre of Excellence [RE/13/6/30180], K.D. is funded as a HSST trainee by NHS Health Education England, S.E. is supported by a fellowship from La Caixa, V.P. is supported by a FEBS long-term fellowship and N.S.'s research is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510) and the NIHR BRC. The Blood and Transplant Unit (BTRU) in Donor Health and Genomics is part of and funded by the National Institute for Health Research (NIHR) and is a partnership between the University of Cambridge and NHS Blood and Transplant (NHSBT) in collaboration with the University of Oxford and the Wellcome Trust Sanger Institute. The T-cell data was produced by the McGill Epigenomics Mapping Centre (EMC McGill). It is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec (CIHR EP1-120608), with additional support from Genome Canada and FRSQ. T.P. holds a Canada Research Chair.