Principal Investigator: Professor Kari Stefansson
deCODE genetics ehf, CEO, Sturlugata 8, Reykjavik IS101, IcelandTags: 23359, Association, genes, osteoarthritis, total joint replacements
Lead Collaborators: Professor John Loughlin
Collaborating Institutions and Addresses: Newcastle University, Institute of Cellular Medicine, 4th Floor Catherine Cookson Bldg, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom
1a: Osteoarthritis is a common form of musculoskeletal disability and is responsible for an increasing global health burden. Osteoarthritis is highly heritable and several genetic variants have been found to associate with the disease. Identifying additional variants will contribute to the understanding of the disease and may provide new targets for drug development.
We seek to established robust associations between DNA variants and osteoarthritis. This application requests data for osteoarthritis patients and controls from UK Biobank as well as data from individuals that may serve as matched controls for the UK osteoarthritis patient collection of arcOGEN funded by Arthritis Research UK.
1b: Identifying additional sequence variants in the genome that associate with osteoarthritis will contribute to increased understanding of the disease and may provide new targets for drug development.
In addition to providing data on osteoarthritis cases and controls the UK Biobank can also leverage on a previous UK study that focused on recruiting osteoarthritis cases only, the arcOGEN study, with controls.
A whole genome amplification of the received DNA samples will be done. This allows many more markers to be genotyped on each sample than otherwise possible with the small amount of DNA, thus making best use of this limited resource.
1c: Whole genome data will be attained for the study subjects and genotype frequencies will be compared between osteoarthritis patients and controls in a genome wide association study. Markers that associate in Iceland will be specifically selected from the results to investigate replication of their association in the UK.
The UK dataset and Icelandic datasets will subsequently be joined in a larger meta-analyses effort.
The study subjects DNA will be used for direct genotyping of those markers that are not included on the UK Biobank genotyping dataset (genotyped or well imputed).
1d: A subset of the UK Biobank samples are requested; genotypes and DNA samples from individuals who have been diagnosed with osteoarthritis of the hip, knee or in other joints or have undergone total joint replacement because of osteoarthritis. After exclusion and accounting for overlap the total number of individuals is expected to be 35,000.
Controls will be shared with application 24299, 19,000 samples in total (including cases). After excluding osteoarthritis cases from these samples, additional control samples to match the final number of cases in this application is requested as well as control samples for the arcOGEN study.
Application 23359 focusses on osteoarthritis, primarily of replication of association signals in Iceland and subsequent meta-analysis of the Icelandic and UK data. Bone mineral density and bone shape, both accessed by DXA, have been linked to osteoarthritis (PMIDs: 24196872, 21400473, 22544526, 22566624), and an inverse relationship has been observed between osteoarthritis of the hip and fractures at the hip as well as the location of the fracture in the proximal femur (PMIDs: 24500824, 23203458, 2425353).
In our recent unpublished study of bone shape as assessed by DXA (area) we have found several loci that associate with both osteoarthritis, fractures, and bone mineral density (DXA assessment). We wish to replicate those findings also for fractures and DXA measures in the UK Biobank data, as we do for osteoarthritis, and therefore, wish to extend the application 23359 to these phenotypes.