A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

Molecular Psychiatry
O S CohenS J Glatt

Abstract

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

References

Dec 10, 2003·Archives of General Psychiatry·Patrick F SullivanMichael C Neale
Jan 24, 2004·American Journal of Human Genetics·Christoph LangeNan M Laird
Sep 24, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Diego CentonzePaolo Calabresi
Jan 13, 2006·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Stephen J Glatt, Erik G Jönsson
Mar 21, 2007·Progress in Neuro-psychopharmacology & Biological Psychiatry·Chao DengXu-Feng Huang
Dec 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ying ZhangWolfgang Sadée
Oct 3, 2008·Brain : a Journal of Neurology·Alessandro BertolinoWolfgang Sadee
Apr 28, 2009·Neuroscience·A Bertolino, G Blasi
Nov 27, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Giuseppe BlasiAlessandro Bertolino
Jan 16, 2010·The Australian and New Zealand Journal of Psychiatry·Cynthia Shannon WeickertClive Harper
Jul 21, 2010·Clinical Schizophrenia & Related Psychoses·Philip Seeman
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·Giuseppe BlasiAlessandro Bertolino
Sep 17, 2011·Human Mutation·Francesco PivaGiovanni Principato
Nov 1, 2011·Nature Genetics·Yongyong ShiLin He
May 14, 2014·PloS One·Annabella Di GiorgioAlessandro Bertolino
Jul 25, 2014·Nature·UNKNOWN Schizophrenia Working Group of the Psychiatric Genomics Consortium

❮ Previous
Next ❯

Citations

Jan 20, 2018·Nature Communications·Jan RozmanMartin Hrabe de Angelis
Jan 6, 2016·The Journal of Cell Biology·Benoit Chabot, Lulzim Shkreta
Oct 21, 2017·Genes, Brain, and Behavior·E RebleC L Barr
Mar 18, 2021·Neuroscience Letters·Akinsola Raphael AkinyemiQiang Liu
May 1, 2021·International Journal of Molecular Sciences·Luca MagistrelliFranca Marino
Apr 11, 2020·Chemical Research in Toxicology·Mayukh BanerjeeJ Christopher States

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alternative splicing

Alternative splicing a regulated gene expression process that allows a single genetic sequence to code for multiple proteins. Here is that latest research.