dc.contributor.author | Curtis, D | en_US |
dc.contributor.author | Coelewij, L | en_US |
dc.contributor.author | Liu, S-H | en_US |
dc.contributor.author | Humphrey, J | en_US |
dc.contributor.author | Mott, R | en_US |
dc.date.accessioned | 2018-03-26T08:35:46Z | |
dc.date.available | 2018-03-13 | en_US |
dc.date.issued | 2018-05 | en_US |
dc.date.submitted | 2018-03-25T17:14:14.564Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/36085 | |
dc.description.abstract | A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the "FMRP targets" set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a "prioritized candidate gene". Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP = 1.7) and GRIN2B (SLP = 2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, three were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees. | en_US |
dc.description.sponsorship | Samples used for data analysis
were provided by the Swedish Cohort Collection supported by the
NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the
Stanley Medical Research Institute and The Swedish Research Council
(Grants 2009-4959 and 2011-4659). Support for the exome sequencing
was provided by the NIMH Grand Opportunity grant RCMH089905,
the Sylvan C. Herman Foundation, a grant from the Stanley Medical
Research Institute and multiple gifts to the Stanley Center for Psychiatric
Research at the Broad Institute of MIT and Harvard. JH is supported
by MRC studentship 516702. | en_US |
dc.format.extent | 198 - 208 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Behav Genet | en_US |
dc.rights | CC BY | |
dc.subject | Exome | en_US |
dc.subject | FYN, FMRP target | en_US |
dc.subject | Gene | en_US |
dc.subject | Schizophrenia | en_US |
dc.subject | Weighted burden test | en_US |
dc.subject | Case-Control Studies | en_US |
dc.subject | Databases, Genetic | en_US |
dc.subject | Gene Ontology | en_US |
dc.subject | Genetic Predisposition to Disease | en_US |
dc.subject | Humans | en_US |
dc.subject | Schizophrenia | en_US |
dc.subject | Sweden | en_US |
dc.subject | Synapses | en_US |
dc.subject | Whole Exome Sequencing | en_US |
dc.title | Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology. | en_US |
dc.type | Article | |
dc.rights.holder | © The Author(s) 2018. | |
dc.identifier.doi | 10.1007/s10519-018-9893-3 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29564678 | en_US |
pubs.issue | 3 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 48 | en_US |
dcterms.dateAccepted | 2018-03-13 | en_US |