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Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia

Leonenko, G; Richards, AL; Walters, JT; Pocklington, A; Chambert, K; Al Eissa, MM; Sharp, SI; ... O'Donovan, MC; + view all (2017) Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics , 174 (7) pp. 724-731. 10.1002/ajmg.b.32560. Green open access

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Abstract

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies.

Type: Article
Title: Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/ajmg.b.32560
Publisher version: http://doi.org/10.1002/ajmg.b.32560
Language: English
Additional information: Copyright © 2017 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: FMRP, association, exome chip, rare variation, schizophrenia
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/1566860
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