The MIR137 VNTR rs58335419 Is Associated With Cognitive Impairment in Schizophrenia and Altered Cortical Morphology

Abstract

Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA's expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

Keywords: MIR137 VNTR; cognitive deficit; genome sequencing; neuroanatomy; schizophrenia.

Fig. 1.

Association of MIR137 variable number tandem repeat (VNTR) with cognitive deficit subtype. Logistic regression analyses showed that the 4-repeats VNTR (VNTR₄) genotype was enriched in the cognitive deficit subtype (P = .03, odds ratio [OR] = 1.92) but not cognitively spared group (P = .67, OR = 1.15) as compared to the control group. No significant difference was observed between the cognitive deficit and cognitively spared groups (P = .05, OR = 1.69). Also there was no association between the VNTR₄ and diagnostic groups (P = .11, OR= 1.58).

Fig. 2.

Whole-brain gray matter volume changes associated with cognitive subgroups of schizophrenia cases compared to healthy controls (HC). Volume of the left entorhinal gyrus was significantly larger in HC compared to both the cognitively spared (CS) and cognitive deficits (CD) groups (post hoc P < .001). a.u.: arbitrary units; color bar represents F-statistics; coordinates are reported in Montreal Neurologic Institute space; error bars represent 95% CI; VNTR, variable number tandem repeat.

Fig. 3.

Whole-brain surface-based gray matter changes associated with the variable number tandem repeat (VNTR) genotype. Left inferior/middle temporal gyrus (left) and right postcentral sulcus (right) were significantly thicker and deeper, respectively, in 4-repeats VNTR (VNTR4) carriers compared to noncarriers (post hoc P < .001). a.u.: arbitrary units; color bar represents P-value; error bars represent 95% CI.