Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies have uncovered hundreds of DNA changes associated with complex disease. The ultimate promise of these studies is the understanding of disease biology; this goal, however, is not easily achieved because each disease has yielded numerous associations, each one pointing to a region of the genome, rather than a specific causal mutation. Presumably, the causal variants affect components of common molecular processes, and a first step in understanding the disease biology perturbed in patients is to identify connections among regions associated to disease. Since it has been reported in numerous Mendelian diseases that protein products of causal genes tend to physically bind each other, we chose to approach this problem using known protein–protein interactions to test whether any of the products of genes in five complex trait-associated loci bind each other. We applied several permutation methods and find robustly significant connectivity within four of the traits. In Crohn's disease and rheumatoid arthritis, we are able to show that these genes are co-expressed and that other proteins emerging in the network are enriched for association to disease. These findings suggest that, for the complex traits studied here, associated loci contain variants that affect common molecular processes, rather than distinct mechanisms specific to each association.Massachusetts Institute of Technology (MIT IDEA2 Program)Harvard University. Biological and Biomedical Sciences ProgramEunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (NICHD RO1 grant HD055150-03)National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (K08 NIH-NIAMS career development award (AR055688))National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK083756)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK086502)Denmark. Forskningsradet for Sundhed og SygdomCenter for the Study of Inflammatory Bowel Diseas

Drosophila Duplication Hotspots Are Associated with Late-Replicating Regions of the Genome

Duplications play a significant role in both extremes of the phenotypic spectrum of newly arising mutations: they can have severe deleterious effects (e.g. duplications underlie a variety of diseases) but can also be highly advantageous. The phenotypic potential of newly arisen duplications has stimulated wide interest in both the mutational and selective processes shaping these variants in the genome. Here we take advantage of the Drosophila simulans–Drosophila melanogaster genetic system to further our understanding of both processes. Regarding mutational processes, the study of two closely related species allows investigation of the potential existence of shared duplication hotspots, and the similarities and differences between the two genomes can be used to dissect its underlying causes. Regarding selection, the difference in the effective population size between the two species can be leveraged to ask questions about the strength of selection acting on different classes of duplications. In this study, we conducted a survey of duplication polymorphisms in 14 different lines of D. simulans using tiling microarrays and combined it with an analogous survey for the D. melanogaster genome. By integrating the two datasets, we identified duplication hotspots conserved between the two species. However, unlike the duplication hotspots identified in mammalian genomes, Drosophila duplication hotspots are not associated with sequences of high sequence identity capable of mediating non-allelic homologous recombination. Instead, Drosophila duplication hotspots are associated with late-replicating regions of the genome, suggesting a link between DNA replication and duplication rates. We also found evidence supporting a higher effectiveness of selection on duplications in D. simulans than in D. melanogaster. This is also true for duplications segregating at high frequency, where we find evidence in D. simulans that a sizeable fraction of these mutations is being driven to fixation by positive selection

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P &lt; 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.</p

The Rotterdam Study: 2010 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods