LAUSR

Abstract Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, are associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognition, brain structure and brain function. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. In a sample of 808 patients and 192 controls, we tested whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory performance, and brain volume and cortical thickness and shape analysis was carried out in n=216 patients and healthy participants. Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance measures of IQ, working memory and episodic memory. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10-5) was significantly associated with increased activation of the right inferior occipital gyrus. Finally, the MiR137 gene network was not associated with variation in cortical thickness or shape, nor was it associated with variation in hippocampal volume. While polygenic risk scores were associated with reduced whole brain volume, this finding did not survive correction for multiple testing. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate, in part, to its broader downstream genetic effects on neurocognitive function.