Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.
Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were...
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2011
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oai:doaj.org-article:fc8f88c9f5314babada323faa5b3d3512021-11-18T06:54:39ZClustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.1932-620310.1371/journal.pone.0019011https://doaj.org/article/fc8f88c9f5314babada323faa5b3d3512011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21559497/?tool=EBIhttps://doaj.org/toc/1932-6203Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.René A W FrankAllan F McRaeAndrew J PocklingtonLouie N van de LagemaatPau NavarroMike D R CroningNoboru H KomiyamaSophie J BradleyR A John ChallissJ Douglas ArmstrongRobert D FinnMary P MalloyAlan W MacLeanSarah E HarrisJohn M StarrSanjeev S BhaskarEleanor K HowardSarah E HuntAlison J CoffeyVenkatesh RanganathPanos DeloukasJane RogersWalter J MuirIan J DearyDouglas H BlackwoodPeter M VisscherSeth G N GrantPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19011 (2011) |
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| spellingShingle |
Medicine R Science Q René A W Frank Allan F McRae Andrew J Pocklington Louie N van de Lagemaat Pau Navarro Mike D R Croning Noboru H Komiyama Sophie J Bradley R A John Challiss J Douglas Armstrong Robert D Finn Mary P Malloy Alan W MacLean Sarah E Harris John M Starr Sanjeev S Bhaskar Eleanor K Howard Sarah E Hunt Alison J Coffey Venkatesh Ranganath Panos Deloukas Jane Rogers Walter J Muir Ian J Deary Douglas H Blackwood Peter M Visscher Seth G N Grant Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| description |
Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders. |
| format |
article |
| author |
René A W Frank Allan F McRae Andrew J Pocklington Louie N van de Lagemaat Pau Navarro Mike D R Croning Noboru H Komiyama Sophie J Bradley R A John Challiss J Douglas Armstrong Robert D Finn Mary P Malloy Alan W MacLean Sarah E Harris John M Starr Sanjeev S Bhaskar Eleanor K Howard Sarah E Hunt Alison J Coffey Venkatesh Ranganath Panos Deloukas Jane Rogers Walter J Muir Ian J Deary Douglas H Blackwood Peter M Visscher Seth G N Grant |
| author_facet |
René A W Frank Allan F McRae Andrew J Pocklington Louie N van de Lagemaat Pau Navarro Mike D R Croning Noboru H Komiyama Sophie J Bradley R A John Challiss J Douglas Armstrong Robert D Finn Mary P Malloy Alan W MacLean Sarah E Harris John M Starr Sanjeev S Bhaskar Eleanor K Howard Sarah E Hunt Alison J Coffey Venkatesh Ranganath Panos Deloukas Jane Rogers Walter J Muir Ian J Deary Douglas H Blackwood Peter M Visscher Seth G N Grant |
| author_sort |
René A W Frank |
| title |
Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| title_short |
Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| title_full |
Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| title_fullStr |
Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| title_full_unstemmed |
Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| title_sort |
clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/fc8f88c9f5314babada323faa5b3d351 |
| work_keys_str_mv |
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