title: MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls.
abstract: Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been 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 cognitive performance. 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. We then tested, in a sample of 808 patients and 192 controls, 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 (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. 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. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.
authors.affiliation: The Cognitive Genetics & Cognitive Therapy Group, The School of Psychology and Discipline of Biochemistry, The Centre for Neuroimaging & Cognitive Genomics, National University of Ireland, Galway, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: Cosgrove
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: Harold
authors.affiliation: The Cognitive Genetics & Cognitive Therapy Group, The School of Psychology and Discipline of Biochemistry, The Centre for Neuroimaging & Cognitive Genomics, National University of Ireland, Galway, Ireland.
authors.forename: O
authors.initials: O
authors.lastname: Mothersill
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.|Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: R
authors.initials: R
authors.lastname: Anney
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hill
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Bray
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Blokland
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Petryshen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: A
authors.initials: A
authors.lastname: Richards
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: K
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: M
authors.initials: M
authors.lastname: Owen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Corvin
authors.affiliation: The Cognitive Genetics & Cognitive Therapy Group, The School of Psychology and Discipline of Biochemistry, The Centre for Neuroimaging & Cognitive Genomics, National University of Ireland, Galway, Ireland.
authors.forename: D W
authors.initials: DW
authors.lastname: Morris
authors.affiliation: The Cognitive Genetics & Cognitive Therapy Group, The School of Psychology and Discipline of Biochemistry, The Centre for Neuroimaging & Cognitive Genomics, National University of Ireland, Galway, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Donohoe
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D016022:Case-Control Studies; D003071:Cognition; D000066499:Facial Recognition; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory; D061212:Memory, Episodic; D008570:Memory, Short-Term; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D012565:Schizophrenic Psychology; D013647:Task Performance and Analysis; D055815:Young Adult
chemical_list: C545567:MIRN137 microRNA, human; D035683:MicroRNAs