Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology

Autor:	Leda Coelewij, Richard Mott, Jack Humphrey, Shou-Hwa Liu, David Curtis
Rok vydání:	2018
Předmět:	Weighted burden test 0301 basic medicine Candidate gene Genome-wide association study Gene 03 medical and health sciences symbols.namesake 0302 clinical medicine FYN Databases Genetic Exome Sequencing Genetics Humans Exome Genetic Predisposition to Disease FYN FMRP target Genetics (clinical) Ecology Evolution Behavior and Systematics Original Research 030304 developmental biology Sweden 0303 health sciences biology GRIN1 Gene Ontology 030104 developmental biology Bonferroni correction Case-Control Studies Synapses Schizophrenia symbols biology.protein GRIN2B 030217 neurology & neurosurgery
Zdroj:	Behavior Genetics
ISSN:	1573-3297 0001-8244
DOI:	10.1007/s10519-018-9893-3
Popis:	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. Electronic supplementary material The online version of this article (10.1007/s10519-018-9893-3) contains supplementary material, which is available to authorized users.
Databáze:	OpenAIRE
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