Association of genetic variation in the MET proto-oncogene with schizophrenia and general cognitive ability

Abstract

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.

Method: 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.

Conclusion: 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.

Figure 1. Linkage Disequilibrium Structure of MET Haplotype Blocks in the Initial Sample

Linkage disequilibrium (D′) for the region typed using Haploview 3.32 (24).

Figure 2. Effects of MET on General Cognitive Ability in the Combined Sample

The X-axis labels the subject groups by MET genotype. The Y-axis represents the composite g using a z-score scale with a mean of 0 and SD of 1. The effect of MET GCAATACA on neurocognition is significant in the healthy control sample (p=0.05) but not in the schizophrenia sample (p=0.23).