John M Lynch

Publications of John M Lynch

• Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

  Authors: Gianpiero L Cavalleri, Michael E Weale, Kevin V Shianna, Rinki Singh, John M Lynch, Bronwyn Grinton, Cassandra Szoeke, Kevin Murphy, Peter Kinirons, Deirdre O'Rourke [......] Terence J O'Brien, Josemir W Sander, John S Duncan, Ingrid E Scheffer, Samuel F Berkovic, Nicholas W Wood, Colin P Doherty, Norman Delanty, Sanjay M Sisodiya, David B Goldstein

  Lancet neurology. 12/2007; 6(11):970-80.

  BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development andBACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

• A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy.

  Authors: Gianpiero L Cavalleri, Nicole M Walley, Nicole Soranzo, John Mulley, Colin P Doherty, Ashish Kapoor, Chantal Depondt, John M Lynch, Ingrid E Scheffer, Armin Heils [......] Peter Kinirons, Sonia Gandhi, Parthasarathy Satishchandra, Nicholas W Wood, Anuranjan Anand, Thomas Sander, Samuel F Berkovic, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Epilepsia. 05/2007; 48(4):706-12.

  PURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recentlyPURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls. METHODS: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. RESULTS: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region. CONCLUSIONS: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

• Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.

  Authors: Naheed L Khan, Shushant Jain, John M Lynch, Nicola Pavese, Patrick Abou-Sleiman, Janice L Holton, Daniel G Healy, William P Gilks, Mary G Sweeney, Milan Ganguly [......] Tamas Revesz, David Nicholl, Kailash P Bhatia, Niall Quinn, David Brooks, Andrew J Lees, Mary B Davis, Paola Piccini, Andrew B Singleton, Nicholas W Wood

  Brain : a journal of neurology. 01/2006; 128(Pt 12):2786-96.

  We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson'sWe have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.

• Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?

  Authors: Gianpiero L Cavalleri, John M Lynch, Chantal Depondt, Mari-Wyn Burley, Nicholas W Wood, Sanjay M Sisodiya, David B Goldstein

  Brain : a journal of neurology. 09/2005; 128(Pt 8):1832-40.

  Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic riskTemporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.