Journal
MOLECULAR PSYCHIATRY
Volume 21, Issue 7, Pages 975-982Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2015.137
Keywords
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Funding
- US National Institutes of Health [R01MH085521]
- Gerber Foundation
- National Health Research Institute of Taiwan [90-8825PP, 91,92-9113PP]
- National Taiwan University [97R00066-47,48]
- Genomic Medicine Research Program of Psychiatric Disorders of National Taiwan University Hospital
- National Research Program for Genomic Medicine of the National Science Council of Taiwan [NSC-94-3112-B-002, NSC-95-3112-B-002-011, NSC-96-3112-B-002-011, NSC-97-3112-B-002-046]
- National Natural Science Foundation of China [30530290, 30870896]
- National High Technology Research and Development Program of China [2006AA02Z195, 2008AA02Z401]
- National Basic Research Program of China [2007CB512301]
- National Health Research Institutes of Zhunan, Taiwan
- National Program 863 of China [2006AA02A407]
- National 973 Program of China [2004CB518601]
- International S&T Cooperation Program of China [2006DFA31440]
- Schizophrenia Research Institute (NSW Ministry of Health)
- Schizophrenia Research Institute (Macquarie Group Foundation)
- University of New South Wales
- Neuroscience Research Australia
- National Health and Medical Research Council (Australia)
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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.
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