Effects of MiR‐137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls

Abstract

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure.

Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort

“…PRS based on biologically driven gene-sets may outperform the genome-wide PRS in explaining brain phenotypes. Examples of that are recent studies attempting to identify 'core gene-sets' that make a larger contribution to SZ risk 17 , or to predict brain anatomy 18 and functional connectivity 19 via PRS limited to genes up-or down-regulated by MIR137 20 .…”

Effects of complement gene‐set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls

“…Structural MRI sequences were acquired on a Philips Intera Achieva 3TMR system, with whole‐brain imaging consisting of a T1‐weight image (180 slices; duration 6 min) using a TFE gradient echo pulse sequence, with a slice thickness of 0.9 mm, and 230 × 230 FOV (Cosgrove et al, 2018).…”

“…This software automatically detects the gray matter and white matter volumes of all brain structures, by segmenting subcortical structures by affine registration to Talairach space according to the differences in their voxel intensities, as described elsewhere (Akudjedu et al, 2018; Dale, Fischl, & Sereno, 1999; Fischl et al, 2002). Each image underwent motion correction, intensity normalization, transformation to Talairach space and skull stripping (Cosgrove et al, 2018). Mathematical outliers were detected by using R software as per the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) protocol (http://enigma.loni.ucla.edu/protocols/).…”

Cell type-specific and cross-population polygenic risk score analyses of MIR137 gene pathway in schizophrenia

“…Neuronal MIR137 target genes better explain SZ risk variance than genes with expression altered in vitro by MIR137 Genes with expression altered by either over-expression or knocking-down of MIR137 in NPCs have been recently used to correlate PRS to SZ-related cognitive phenotypes (Cosgrove et al, 2017(Cosgrove et al, , 2018. Given the known weak expression correlation of MIR137 and its targeted genes (Forrest et al, 2017;Topol et al, 2016), we hypothesized that predicted MIR137 gene targets specifically expressed in a disease-relevant cell type may constitute a better gene set for PRS analysis.…”