Weighted burden analysis of exome-sequenced case-control sample implicates synaptic genes in schizophrenia aetiology
By
David Curtis,
Leda Coelewij,
Shou-Hwa Liu,
Jack Humphrey,
Richard Mott
Posted 15 Oct 2017
bioRxiv DOI: 10.1101/203521
(published DOI: 10.1007/s10519-018-9893-3)
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, 3 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.
Download data
- Downloaded 583 times
- Download rankings, all-time:
- Site-wide: 86,682
- In genetics: 3,292
- Year to date:
- Site-wide: None
- Since beginning of last month:
- Site-wide: 209,209
Altmetric data
Downloads over time
Distribution of downloads per paper, site-wide
PanLingua
News
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!