Dr Nigel Williams
Based at the MRC Centre in Neuropsychiatric Genetics and Genomics, School of Medicine
Research Keywords
Genetics of Parkinson’s disease, copy number variants (in particularly 22q11DS), neurodevelopmental phenotypes.
Research Interests and Facilities
Parkinson’s disease (PD) is the second most common neurodegenerative disease, and is characterized by bradykinesia with resting tremor, stiffness and gait disturbance. The population prevalence is estimated at 0.3% but this increases with age; rising to 1-2% in people over 60 and 3-4% in people over 80 years of age. While the average age at onset is 68 years old the onset is extremely variable ranging from adolescence to old age. The identification of rare highly penetrant mutations in genes causing familial PD has had a considerable impact on our understanding of the pathogenesis of this complex and common disorder. More recently our understanding of the idiopathic form PD has been greatly enhanced by a number of large, genome-wide association studies which, as well as providing evidence that variants at the genes encoding α-synuclein and the microtubule-associated protein tau are also risk factors for the idiopathic form of the illness have collectively identified variants at over 18 loci that significantly increase risk for PD. Despite this progress these risk loci are thought to account for only a very small amount (1-2%) of the expected heritability of PD and as in other complex disorders, the 'missing heritability' is expected to relate to a combination of some variants that only yield relatively weak association signals and others that are not tagged by the genotyping microarray. My research is focussed on both identifying further genetic risk factors for PD through large scale exome sequencing and also obtaining a further understanding of the disease aetiology inferred by the risk factors already implicated.
There is now clear evidence that large submicroscopic structural variants including rare copy number variants (CNVs) contribute to other neuropsychiatric disorders including schizophrenia, autism and ADHD. In particular it is now well established that people with deletions at chromosome 22q11 have a greatly increased risk of developing neuropsychiatric phenotypes, and in particular cognitive impairment, ADHD and schizophrenia. There is still little clear understanding of how heterozygous microdeletions at 22q11 lead to the spectrum of behavioural phenotypes and as a result my research aims to elucidate the complex pathogenic mechanisms conferred by these chromosomal abnormalities.
Facilities at the MRC Centre in Neuropsychiatric Genetics and Genomics genetics laboratories include ABI Prism 3100 sequencers, Thermocyclers, Illumina high throughput Genotyping Platform, ABI PRISM 7700, LightScanner mutation detection system, plate reading spectrophotometers and fluorometers, Beckman robotic liquid handling systems.
Available PhD Projects
- Identification of genetic risk factors for Young onset Parkinson’s disease.
- The identification of biological pathways implicated by susceptibility genes for Parkinson's disease.
- An investigation of changes in gene-expression conferred by the deletions at 22q11.
Publications
- Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, Stefansson H, Stefansson K, Magnusson P, Gudmundsson OO, Gustafsson O, Holmans P, Owen MJ, O'Donovan M, Thapar A. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet. 2010 Oct 23;376(9750):1401-8. Epub 2010 Sep 29.
- UK Parkinson's Disease Consortium; Wellcome Trust Case Control Consortium 2, Spencer CC, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G, Barker RA, Bellenguez C, Bhatia K, Blackburn H, Blackwell JM, Bramon E, Brown MA, Brown MA, Burn D, Casas JP, Chinnery PF, Clarke CE, Corvin A, Craddock N, Deloukas P, Edkins S, Evans J, Freeman C, Gray E, Hardy J, Hudson G, Hunt S, Jankowski J, Langford C, Lees AJ, Markus HS, Mathew CG, McCarthy MI, Morrison KE, Palmer CN, Pearson JP, Peltonen L, Pirinen M, Plomin R, Potter S, Rautanen A, Sawcer SJ, Su Z, Trembath RC, Viswanathan AC, Williams NW, Morris HR, Donnelly P, Wood NW. Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet. 2011 Jan 15;20(2):345-53. Epub 2010 Nov 2.
- Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, Thapar A, O'Donovan MC, Owen MJ, Holmans P, Kent L, Middleton F, Zhang-James Y, Liu L, Meyer J, Nguyen TT, Romanos J, Romanos M, Seitz C, Renner TJ, Walitza S, Warnke A, Palmason H, Buitelaar J, Rommelse N, Vasquez AA, Hawi Z, Langley K, Sergeant J, Steinhausen HC, Roeyers H, Biederman J, Zaharieva I, Hakonarson H, Elia J, Lionel AC, Crosbie J, Marshall CR, Schachar R, Scherer SW, Todorov A, Smalley SL, Loo S, Nelson S, Shtir C, Asherson P, Reif A, Lesch KP, Faraone SV. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry. 2012 Feb;169(2):195-204.
- Simón-Sánchez J, Kilarski LL, Nalls MA, Martinez M, Schulte C, Holmans P; International Parkinson's Disease Genomics Consortium; Wellcome Trust Case Control Consortium, Gasser T, Hardy J, Singleton AB, Wood NW, Brice A, Heutink P, Williams N, Morris HR. Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease. PLoS One. 2012;7(3):e28787. Epub 2012 Mar 12.
- Williams NM. Molecular mechanisms in 22q11 deletion syndrome. Schizophr Bull. 2011 Sep;37(5):882-9.