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Institute of Medical Sciences

Molecular Genetics

Contact: Dr Lynne Hocking, Research Fellow (Email: l.hocking@abdn.ac.uk, Tel: +44(0)1224 555162)

Genetic variation that we inherit from our parents and pass on to our children contributes to many disorders of the Musculoskeletal system, including osteoporosis, congenital talipes equinovarus (idiopathic clubfoot), rheumatoid arthritis, osteoarthritis, Paget's disease of bone, osteopetrosis and chronic pain. If we can identify the genetic variants that predispose individuals to developing these disorders, then we can target specific treatment and/or lifestyle advice to those people most likely to benefit from it. In addition, knowledge of how these variations affect bone cells can help to identify new targets for the development of future treatments.

The major goals of our research are to identify and understand:

  • The genes important in development or progression of musculoskeletal disorders, including osteoporosis, idiopathic clubfoot, rheumatoid arthritis and chronic pain.
  • The genes that control or influence normal bone turnover, post-menopausal bone loss, and susceptibility to falls and fracture.

We use both family- and population-based approaches to identify these genetic variants, using DNA samples that have been generously provided by individuals and their families affected with clubfoot and rheumatoid arthritis. We also use DNA samples from healthy adults for whom we have clinical measurements of bone density, bone turnover and musculoskeletal pain, along with measures of environmental factors that may be important in the development or progression of osteoporosis or fractures, such as diet, physical activity and falls.

We also participate in national and international collaborations; Generation Scotland and GENOMOS/GEFOS. Generation Scotland is a unique partnership between the Scottish University Medical Schools, Biomedical Research Institutes, the NHS in Scotland and the people of Scotland. Its focus is to identify the genetic basis of many common disorders such as cancer, heart disease, stroke, mental health problems and musculoskeletal disorders. GENOMOS is an EU-sponsored FP6 project on the genetics of osteoporosis that has expanded into a research collaboration between twenty research groups worldwide; GEFOS is the FP7 successor of GENOMOS.

Research interests: osteoporosis, rheumatoid arthritis, idiopathic clubfoot, chronic pain, Paget's disease of bone, regulation of bone mineral density and bone turnover, gene-nutrient interactions, gene-environment interactions.

Research funded by: Generation Scotland, Arthritis Research Campaign, National Association for Research into Paget's Disease, Medical Research Scotland (formerly SHERT), Food Standards Agency, Sport Aiding Medical Research for Kids (SPARKS).

Additional data kindly provided by the 1958 Birth Cohort and Wellcome Trust Case Control Consortium.

Personnel

Selected Publications

Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J, Gibbons L, Plant D; Wellcome Trust Case Control Consortium, Wilson AG, Marinou I, Morgan A, Emery P; YEAR consortium, Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Worthington J (2008) Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Human Molecular Genetics doi:10.1093/hmg/ddn128

Liu G, Inglis J, Cardy A, Shaw D, Sahota S, Hennekam R, Sharp L, Miedzybrodzka Z (2008) Variation in WNT7A is unlikely to be a cause of familial Congenital Talipes Equinovarus. BMC Medical Genetics 9: 50

Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD, Ralston SH, Reid DM (2008) Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms. American Journal of Clinical Nutrition 87: 1513-1520

van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG; GENOMOS Study (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299: 1277-90

Lucas GJ, Riches PL, Hocking LJ, Cundy T, Nicholson GC, Walsh JP, Ralston SH. Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent (2008) Journal of Bone and Mineral Research 23: 58-63

Cardy AH, Barker S, Chesney D, Sharp L, Maffulli N, Miedzybrodzka Z (2007) Pedigree analysis and epidemiological features of idiopathic congenital talipes equinovarus in the United Kingdom: a case-control study. BMC Musculoskeletal Disorders 8: 62

Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, Donn R, Symmons D, Hider S, Bruce IN; Wellcome Trust Case Control Consortium, Wilson AG, Marinou I, Morgan A, Emery P; YEAR Consortium, Carter A, Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Strachan D, Worthington J (2007) Rheumatoid arthritis association at 6q23. Nature Genetics 39: 1431-1433

McGuigan FE, Macdonald HM, Bassiti A, Farmer R, Bear S, Stewart A, Black A, Fraser WD, Welsh F, Reid DM, Ralston SH (2007) Large-scale population-based study shows no association between common polymorphisms of the TGFB1 gene and BMD in women. Journal of Bone and Mineral Research 22: 195-202

Sharp L, Miedzybrodzka Z, Cardy AH, Inglis J, Madrigal L, Barker S, Chesney D, Clark C, Maffulli N (2006) The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR), maternal use of folic acid supplements, and risk of isolated clubfoot: A case-parent-triad analysis. American Journal of Epidemiology 164: 852-861

Macdonald HM, McGuigan FE, Stewart A, Black AJ, Fraser WD, Ralston S, Reid DM. (2006) Large-scale population-based study shows no evidence of association between common polymorphism of the VDR gene and BMD in British women. Journal of Bone and Mineral Research 21: 151-162

Parsons CA, Mroczkowski HJ, McGuigan FE, Albagha OM, Manolagas S, Reid DM, Ralston SH, Shmookler Reis RJ. (2005) Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Human Molecular Genetics 14: 3141-3148

Hocking LJ, Lucas GJ, Daroszewska A, Cundy T, Nicholson GC, Donath J, Walsh JP, Finlayson C, Cavey JR, Ciani B, Sheppard PW, Searle MS, Layfield R, Ralston SH (2004) Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences. Journal of Bone and Mineral Research 19: 1122-1127

Macdonald HM, McGuigan FE, Fraser WD, New SA, Ralston SH, Reid DM. (2004) Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density. Bone 35: 957-964

Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W and Ralston SH (2002) Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Human Molecular Genetics 11: 2735-2739

Hocking LJ, Herbert CA, Nicholls RK, Williams F, Bennett ST, Cundy T, Nicholson GC, Wuyts W, Van Hul W and Ralston SH (2001) Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35. American Journal of Human Genetics 69: 1055-1061

MacDonald HM, McGuigan FA, New SA, Campbell MK, Golden MH, Ralston SH, Reid DM. (2001) COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss. Journal of Bone and Mineral Research 16: 1634-1641

Selected Reviews

Helfrich MH, Hocking LJ (2008) Genetics and aetiology of Pagetic disorders of bone. Archives of Biochemistry and Biophysics 473: 172-182

Miedzybrodzka Z (2003) Congenital talipes equinovarus (clubfoot): a disorder of the foot but not the hand. Journal of Anatomy 202: 37-42