| Title: |
Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia |
| Authors: |
Leonenko, Ganna; Richards, Alexander L.; Walters, James T.; Pocklington, Andrew; Chambert, Kimberly; Al Eissa, Mariam M.; Sharp, Sally I.; O'Brien, Niamh L.; Curtis, David; Bass, Nicholas J.; McQuillin, Andrew; Hultman, Christina; Moran, Jennifer L.; McCarroll, Steven A.; Sklar, Pamela; Neale, Benjamin M.; Holmans, Peter A.; Owen, Michael J.; Sullivan, Patrick F.; O'Donovan, Michael C. |
| Publisher Information: |
Wiley |
| Publication Year: |
2017 |
| Collection: |
Cardiff University: ORCA (Online Research @ Cardiff) |
| Description: |
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 |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://orca.cardiff.ac.uk/id/eprint/102723/1/Leonenko_et_al-2017-American_Journal_of_Medical_Genetics_Part_B__Neuropsychiatric_Genetics.pdf; Leonenko, Ganna https://orca.cardiff.ac.uk/view/cardiffauthors/A055950G.html orcid:0000-0001-8025-661X orcid:0000-0001-8025-661X, Richards, Alexander L. https://orca.cardiff.ac.uk/view/cardiffauthors/A092272D.html, Walters, James T. https://orca.cardiff.ac.uk/view/cardiffauthors/A0230062.html orcid:0000-0002-6980-4053 orcid:0000-0002-6980-4053, Pocklington, Andrew https://orca.cardiff.ac.uk/view/cardiffauthors/A164850I.html orcid:0000-0002-2137-0452 orcid:0000-0002-2137-0452, Chambert, Kimberly, Al Eissa, Mariam M., Sharp, Sally I., O'Brien, Niamh L., Curtis, David, Bass, Nicholas J., McQuillin, Andrew, Hultman, Christina, Moran, Jennifer L., McCarroll, Steven A., Sklar, Pamela, Neale, Benjamin M., Holmans, Peter A. https://orca.cardiff.ac.uk/view/cardiffauthors/A0466487.html orcid:0000-0003-0870-9412 orcid:0000-0003-0870-9412, Owen, Michael J. https://orca.cardiff.ac.uk/view/cardiffauthors/A069868J.html orcid:0000-0003-4798-0862 orcid:0000-0003-4798-0862, Sullivan, Patrick F. and O'Donovan, Michael C. https://orca.cardiff.ac.uk/view/cardiffauthors/A038895E.html orcid:0000-0001-7073-2379 orcid:0000-0001-7073-2379 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 https://doi.org/10.1002/ajmg.b.32560 file https://orca.cardiff.ac.uk/id/eprint/102723/1/Leonenko_et_al-2017-American_Journal_of_Medical_Genetics_Part_B__Neuropsychiatric_Genetics.pdf |
| DOI: |
10.1002/ajmg.b.32560 |
| Availability: |
https://orca.cardiff.ac.uk/id/eprint/102723/; https://doi.org/10.1002/ajmg.b.32560 |
| Rights: |
cc_by |
| Accession Number: |
edsbas.B015231C |
| Database: |
BASE |