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4 YEAR PhD IN NEUROSCIENCE

John Hardy

Institute of Neurology

Genomic and cellular investigation of neurodegeneration

Our research interests lie in finding the genes and cellular pathways that cause degeneration. We are primarily a genetics based group and are using a variety of classical and innovative genetics techniques to identify new genes that causal for neurodegeneration in mendelian families, or, more recently, through whole genome analysis. When we have identified mendelian genes or risk loci, we then attempt to understand the ways through which the loci initiate pathogenesis.  To do this, we are employing two innovative techniques. First, in families with mendelian disease we are taking fibroblasts with defined mutations and transforming them through stem cells to neurons.  We are in the middle of this process for LRRK2 and synuclein genes (both Parkinson’s genes which our lab played a part in discovering) and we plan to apply it to the Alzheimer and dementia genes, APP, presenilin 1 and tau genes (we were also responsible for identifying APP and tau mutations).  Second, we and others have found that most risk factor loci influence gene expression rather than causing changes in the amino acid sequence of proteins.  We are therefore creating a genome wide catalogue of the genetic control of gene expression throughout the brain. Our intention is that this catalogue should be a Rosetta stone for the deciphering of the mechanisms by which disease loci initiate pathogenesis.

Available Projects:

Supervisors: Dr Patrick Lewis and Professor John Hardy

Applying biophysical and biochemical approaches to define the folding and turnover properties of the PD linked protein LRRK2, and the impact of mutations on these properties.

Molecular Characterization of Novel PD-associated Loci: Identifying new genes and defining sub-phenotypes. The main goal of this project is to identify all molecular events involved in the pathogenesis of Parkinson’s disease. Currently, two PD-associated GWAS are completed (German and USA studies) and other two are undergoing (French and UK studies). Therefore, a large Meta-Analysis of all GWAS above mentioned will be carried out. This will be followed by  a delineation of all associated haplotypes through target re-sequencing of those candidate, genomic regions. In addition, fine-mapping disease-related segments based on autozygosity will be performed in the young-onset PD cohorts. With all these analyses, we hope to characterize all biochemical pathways underlying disease.

  • Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, Kaleem M, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, Holmans P, Heward CB, Reiman EM, Stephan D, Hardy J. A survey of genetic human cortical gene expression. Nat Genet. 2007 Dec;39(12):1494-9
  • Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR. Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1499-504.

Supervisors: Dr Coro Paisán-Ruiz and Professor John Hardy

Molecular Characterization of Novel PD-associated Loci: Identifying new genes and defining sub-phenotypes

The main goal of this project is to identify all molecular events involved in the pathogenesis of Parkinson’s disease. Currently, two PD-associated GWAS are completed (German and USA studies) and other two are undergoing (French and UK studies). Therefore, a large Meta-Analysis of all GWAS above mentioned will be carried out. This will be followed by  a delineation of all associated haplotypes through target re-sequencing of those candidate, genomic regions. In addition, fine-mapping disease-related segments based on autozygosity will be performed in the young-onset PD cohorts. With all these analyses, we hope to characterize all biochemical pathways underlying disease.

  • Simon-Sanchez J*, Schulte C*, Bras JM*, Sharma MJ*, Gibbs JR, Berg D , Paisan-Ruiz  C, Lichtner  P, Scholz SW, Hernandez DG, Krüger  R, Federoff M , Klein C , Goate A, Joel Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Foote KD, Fernandez HH, Schreiber S, Arepalli S, Zonozi R, Gwinn K, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy J, Singleton AB, Gasser T: Genome-Wide Association Study reveals genetic risk underlying  Parkinson’s disease. Submitted
  • Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C. The genetics of Parkinson's syndromes: a critical review. Curr Opin Genet Dev. 2009 Jun;19(3):254-65.
  • Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med. 2009 Apr 23;360(17):1759-68.
  • Nalls MA*, Simon-Sanchez J*, Gibbs JR, Paisan-Ruiz C, Bras JT, Tanaka T, Matarin M, Scholz S, Weitz C, Harris TB, Ferrucci L, Hardy J, Singleton AB. Measures of autozygosity in decline: globalization, urbanization, and its implications for medical genetics. PLoS Genet. 2009 Mar;5(3):e1000415.
  • Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW, Hardy J, Houlden H, Singleton A, Schneider SA. Characterization of PLA2G6 as a locus for dystonia- parkinsonism. Ann Neuro. 2009 Jan;65(1):19-23

Supervisors: Dr Mina Ryten and Professor John Hardy

Mapping the genetic architecture of global gene and exon expression in the human brain to understand common diseases

The aim of this project is to translate recently discovered genetic risk traits for complex neurological and psychiatric conditions into a deeper understanding of pathogenesis. Using high through-put assays of gene expression and genetic variation we will identify the genetic factors which underpin individual differences in quantitative levels of expression (eQTLs & sQTLs) in the human brain, and use this information to help interpret GWAs (genome-wide association study) “hits”. This project will appeal to people interested in the analysis of large biological data sets and the exciting new field of bioinformatics.

  • Genomewide association studies and human disease. Hardy J, Singleton A. N Engl J Med. 2009 Apr 23;360(17):1759-68. Epub 2009 Apr 15.
  • A survey of genetic human cortical gene expression. Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, Kaleem M, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, Holmans P, Heward CB, Reiman EM, Stephan D, Hardy J. Nat Genet. 2007 Dec;39(12):1494-9. Epub 2007 Nov 4.

More: http://www.ucl.ac.uk/rlweston-inst/Staff-JHardy.html

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