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Identification of genetic and genomic factors underpinning excess risk of rheumatoid arthritis in females


Project Description

Affecting over 400,000 adults in the UK, rheumatoid arthritis (RA) is a common disease that causes pain, swelling and damage in the joints. The prevalence of RA is known to differ between females and males with a sex ratio of approximately 3:1. The reason for this sex bias is poorly understood but genetic and genomic factors are likely to be involved. Recent well-powered genetic studies have identified over 100 genetic regions that are associated with RA development in European and Asian populations (1, 2). However, large scale gender stratified genetic studies in RA are currently lacking.

Genetic variant data will be made available for RA and healthy control subjects through large international collaborations (1). Genome-wide gene expression and DNA methylation data generated in whole blood and single-cell RNA sequencing and Hi-C data generated in peripheral blood PBMCs and T-cells will also be available for a subset of RA patients.

This studentship will investigate the sex bias in RA by taking a number of complementary approaches. Analysis of genetic variant data will identify sex-differentiated genetic effects. Investigating gene expression, DNA methylation and Hi-C data will identify sex-specific expression quantitative trait loci (eQTLs) and transcripts/regions that escape X-chromosome inactivation in female RA patients.

Taken together this studentship will inform how autosomal genetic variation, the x-chromosome and sex underpin excess risk of RA development in females.

Applicants are expected to hold, or about to obtain a minimum upper second class undergraduate degree (or equivalent) in a relevant quantitative subject (e.g. genetics, bioinformatics) and have a strong interest in statistics. A Masters degree in a relevant subject and/or research experience is desirable. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

Funding Notes

This project is funded by Arthritis Research UK Centre for Genetics and Genomics with RCUK stipend. The starting date will be September 2019 for 3 years. If you are interested please make direct contact with the Supervisor to discuss the project. You MUST also submit an application form. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website)

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1) Eyre, Bowes, Diogo et al. Nat Genet. 2012 Dec;44(12):1336-40
2) Tukiainen et al. Nature. 2017 Oct 11;550(7675):244-248
3) Cotton et al. Hum Mol Genet. 2015 Mar 15;24(6):1528-39

https://www.research.manchester.ac.uk/portal/en/facultiesandschools/division-of-musculoskeletal--dermatological-sciences(4040da72-b4fc-41f8-86f4-bea0a665a52a).html

https://www.research.manchester.ac.uk/portal/en/facultiesandschools/division-of-informatics-imaging--data-sciences(3508b831-4d64-4f79-8790-a50df943742c).html

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