Suchergebnisse

OBJECTIVE: Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA. METHODS: A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage. RESULTS: We report suggestive evidence (p0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10-4). CONCLUSIONS: Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity. ; This work was supported by Arthritis Research UK (grant 19542, KP and EZ; grant 20308, KP), the Wellcome Trust (grant 098051, KP and EZ), the Joint Action Trust (grant GA1125, British Orthopaedic Association, ST and JMW) and the National Institute for Health Research funded Sheffield Bone Biomedical Research Unit (ST and JMW). This study used genotype data from arcOGEN (http://www.arcogen.org.uk/) funded by a special purpose grant from Arthritis Research UK (grant 18030). This study makes use of data generated by the Wellcome Trust Case-Control Consortium (the 1958 British Birth Cohort collection and the UK Blood Services Collection). A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk and funding for the project was provided by the Wellcome Trust under awards 076113, 085475 and 090355. The Leiden University Medical Center supports the RAAK Study, while research leading to these results has received funding from the Dutch Arthritis Association (DAA 2010_017) and the IDEAL project (European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679)

Supplementary information is available at http://www.nature.com/ncomms/2014/141106/ncomms6345/extref/ncomms6345-s1.pdf ; Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10−26). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10−36). We demonstrate significant power gains in detecting medical trait associations. ; This work was funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). The TEENAGE study has been supported by the Wellcome Trust (098051), European Union (European Social Fund—ESF) and Greek national funds through the Operational Programme 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)—Research Funding Programme: Heracleitus II, investing in knowledge society through the European Social Fund. G.R.S.R. is supported by the European Molecular Biology Laboratory and the Sanger Institute via an EBI-Sanger Postdoctoral Fellowship. S.F. was supported by H3ABioNet Node, NABDA Abuja Nigeria with NIH Common Fund Award/NHGRI Grant Number U41HG006941 and Genetic Epidemiology Group at WTSI. ; Peer-reviewed ; Publisher Version