Denise Brocklebank

Denise_broclebankMy current research involves the investigation into strategies for imputation-based analysis in GWA studies. This includes the initial design of a resequencing study and factors such as the number of individuals required, the selection of samples for sequencing and optimal use of existing reference panels, such as Internation HapMap resources, for imputation of masked genotypes. Subsequent analysis requires suitable methods and appropriate statistical tools to meet the data generated and determine which variants are potentially causative mutations, and should be included in a follow-on analysis of the full sample.

 

As part of The International-Venezuela HD Collaborative Research Group, I am involved in an on-going study to investigate the genetics of Huntington's in a large Venezuela (Vz) family sample. While Huntington's is a fully penetrant autosomal dominant disorder, many aspects of the course of illness are not well understood. The goal of this project is to identify therapeutic targets for Huntington's Disease by identifying genes which underly genetic variation in HD onset, and thereby also possibly gain insight into the genetic factors influencing other neurodegenerative disorders. The current aim is to follow up a recent GWA association scan performed using the Vz pedigree sample which identified significant and suggestive genetic variants for age of onset. We are now persuing a genome sequence analysis in order to determine where the potential causative variants are located. This phase will entail sequencing of candidate regions identified in the GWA in a select number of individuals. The project poses unique statistical and computing challenges, in particular because it involves use of the very large Venezuelan pedigree on which the HD gene was originally mapped.

 

Selected Publications 

D. Brocklebank, J. Gayán, J. M. Andresen, S. A. Roberts, The International-Venezuela HD Collaborative Research Group, A. B. Young, S. R. Snodgrass, J. B. Penney, M. A. Ramos-Arroyo, J. J. Cha, H. D. Rosas, S. M. Hersch, A.Feigin, S. S. Cherny, N. S. Wexler, D. E. Housman and L. R. Cardon Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: counselling implications. (2009) Am J Med Genet B Neuropsychiatr Genet. Apr 5;150B(3):425

Denise Brocklebank, Fredrik Pettersson, John Broxholme, Adrian V Hill, Andrew P Morris, Andrew J Pollard, Marianne A van der Sande, Giorgio Sirugo, Catrin E. Moore, Branwen J Hennig. (2009) Population structure in West Africans and North West Europeans: a comparison with HapMap data from Yoruba and CEPH Submitted for publication 

Julian E. Asher , Janine A. Lamb , Denise Brocklebank , Jean-Baptiste Cazier , Elena Maestrini , Laura Addis , Mallika Sen , Simon Baron-Cohen and Anthony P. Monaco

A whole-genome scan and fine-mapping linkage study of auditory-visual synesthesia reveals evidence of linkage to chromosomes 2q24, 5q33, 6p12, and 12p12.

 (2009). AJHG  84: 1-7. 

The STAR consortium. (2008) Identification and mapping of single nucleotide polymorphisms for genetic analysis in the rat. Nat Genet. 40(5):560-566 (2008))

Javier Gayán, Denise Brocklebank, J. Michael Andresen, Gorka Alkorta-Aranburu, The US-Venezuela Collaborative Research Group, M. Zameel Cader, Simone A. Roberts, Stacey S. Cherny Nancy S. Wexler, Lon R. Cardon, and David E. Housman􏰈(2008) Genomewide Linkage Scan Reveals NovelCAG Loci Modifying Age of Onset of Huntington's Disease in the Venezuelan HD Kindreds ­Genetic Epidemiology 32:1 -11

Andresen JM, Gayán J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA, Cardon LR, Housman DE, Wexler NS. (2006) Replication of twelve association studies for Huntington's disease residual age of onset in large Venezuelan kindreds. J Med Genet. 44:44-50 

Andresen JM, Gayán J, Djoussé L, Roberts S, Brocklebank, D, Cherny SS, The US-Venezuela Collaborative Research Group, The HD MAPS Collaborative Research Group, Cardon LR, Gusella JF, MacDonald ME, Myers RH, Housman DE, Wexler NS. (2006) The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset. Ann. of Hum. Gen. 71, 295-301.

The U.S.-Venezuela Collaborative Research Project, (2004) Venezuelan kindred's reveal that genetic and environmental factors modulate Huntington's disease age of onset. PNAS, 101, 10 :3498-3503