Association of genetic variation in the MET proto-oncogene with schizophrenia and general cognitive ability.
OBJECTIVE
Despite increased exposure to cancer risk factors, several studies have demonstrated a lower incidence of cancer in schizophrenia patients than in the general population. Lower cancer rates in first-degree relatives of schizophrenia patients suggest that the inverse relationship between cancer and schizophrenia may be related to genetic factors. Few studies of schizophrenia have focused on cancer-related genes. The MET proto-oncogene is primarily linked to tumor metastasis, but MET is also involved in neurodevelopment and influences risk for autism. Thus, MET may be of particular interest as a candidate gene for neuropsychiatric diseases with a developmental etiology, including schizophrenia.


METHODS
The authors examined the relationship between 21 single-nucleotide polymorphisms in MET and schizophrenia in 173 Caucasian patients and 137 comparison subjects. They then genotyped a second independent sample (107 patients and 112 comparison subjects) for replication. Finally, they tested for MET's effects on general cognitive ability (g).


RESULTS
In the initial cohort, the authors identified four haplotype blocks and found one block to be globally associated with schizophrenia. In block 3, the most common haplotype was overrepresented in comparison subjects (frequency, 47%) relative to schizophrenia patients (frequency, 33%) (p=4.0 x 10(-4); odds ratio=0.56). The authors replicated the block 3 finding in the second sample with similar frequencies: 46% in comparison subjects and 36% in schizophrenia patients (p=0.03; odds ratio=0.66). Moreover, the protective haplotype was associated with a higher g in the combined comparison sample.


CONCLUSIONS
These data suggest that MET variation influences schizophrenia risk and neurocognition, supporting a neurodevelopmental role across CNS-relevant phenotypes. These results add to the growing evidence suggesting an intriguing relationship between cancer-related genes and schizophrenia susceptibility.
Burdick
Katherine E
KE
Hillside Hospital, North Shore-Long Island Jewish Health System, Department of Psychiatry Research, Glen Oaks, NY 11004, USA. kburdick@lij.edu
DeRosse
Pamela
P
Kane
John M
JM
Lencz
Todd
T
Malhotra
Anil K
AK
D000328:Adult; D000483:Alleles; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology*; D004261:DNA Replication / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*; D012559:Schizophrenia / Q000453:epidemiology* / Q000235:genetics*; D012720:Severity of Illness Index
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met