Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 affected with schizophrenia – in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. W...

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Main Authors:	Genovese, Giulio, Fromer, Menachem, Stahl, Eli A., Ruderfer, Douglas M., Chambert, Kimberly, Landén, Mikael, Moran, Jennifer L., Purcell, Shaun M., Sklar, Pamela, Sullivan, Patrick F., Hultman, Christina M., McCarroll, Steven A.
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104192/

id	pubmed-5104192
recordtype	oai_dc
spelling	pubmed-51041922017-04-03 Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia Genovese, Giulio Fromer, Menachem Stahl, Eli A. Ruderfer, Douglas M. Chambert, Kimberly Landén, Mikael Moran, Jennifer L. Purcell, Shaun M. Sklar, Pamela Sullivan, Patrick F. Hultman, Christina M. McCarroll, Steven A. Article By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 affected with schizophrenia – in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant in schizophrenia cases than controls (P = 1.3 × 10−10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this genetic signal arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk. 2016-10-03 2016-11 /pmc/articles/PMC5104192/ /pubmed/27694994 http://dx.doi.org/10.1038/nn.4402 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Genovese, Giulio Fromer, Menachem Stahl, Eli A. Ruderfer, Douglas M. Chambert, Kimberly Landén, Mikael Moran, Jennifer L. Purcell, Shaun M. Sklar, Pamela Sullivan, Patrick F. Hultman, Christina M. McCarroll, Steven A.
spellingShingle	Genovese, Giulio Fromer, Menachem Stahl, Eli A. Ruderfer, Douglas M. Chambert, Kimberly Landén, Mikael Moran, Jennifer L. Purcell, Shaun M. Sklar, Pamela Sullivan, Patrick F. Hultman, Christina M. McCarroll, Steven A. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
author_facet	Genovese, Giulio Fromer, Menachem Stahl, Eli A. Ruderfer, Douglas M. Chambert, Kimberly Landén, Mikael Moran, Jennifer L. Purcell, Shaun M. Sklar, Pamela Sullivan, Patrick F. Hultman, Christina M. McCarroll, Steven A.
author_sort	Genovese, Giulio
title	Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
title_short	Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
title_full	Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
title_fullStr	Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
title_full_unstemmed	Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
title_sort	increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
description	By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 affected with schizophrenia – in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant in schizophrenia cases than controls (P = 1.3 × 10−10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this genetic signal arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104192/
_version_	1613721820674916352

Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

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