title: Possibility of a sex-specific role for a genetic variant in FRMPD4 in schizophrenia, but not cognitive function.
abstract: The neurotransmitter disturbances responsible for cognitive dysfunction in schizophrenia are hypothesized to originate with alterations in postsynaptic scaffold proteins. We have recently reported that protein levels of FRMPD4, a multiscaffolding protein that modulates both Homer1 and postsynaptic density protein 95 activity, is altered in the schizophrenia postmortem brain, in regions involved in cognition. Here, we set out to investigate whether genetic variation in FRMPD4 is associated with cognitive function in people with schizophrenia. We selected and examined a novel single nucleotide polymorphism, rs5979717 (positioned in the noncoding 3' untranslated region of FRMPD4 and potentially influencing protein expression), for its association with schizophrenia and nine measures of cognitive function, using age-matched and sex-matched samples from 268 schizophrenia cases and 268 healthy controls. Brain samples from 20 schizophrenia patients and 20 healthy controls were additionally genotyped to study the influence of this variant on protein expression of FRMPD4. Allelic distribution of rs5979717 was associated with schizophrenia in females (χ=4.52, P=0.030). No effects of rs5979717 were observed on cognitive performance, nor an influence of rs5979717 genotypes on the expression of FRMPD4 proteins in postmortem brain samples. These data provide initial support for a sex-specific role for common variation in rs5979717 in schizophrenia, which now warrants further investigation.
authors.affiliation: aSchizophrenia Research Institute bSchool of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney cSchool of Medicine, Faculty of Science, School of Medicine and Health and the Illawarra Health and Medical Research Institute, University of Wollongong dSchool of Psychology, Faculty of Social Sciences, University of Wollongong, Wollongong, New South Wales, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Matosin
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Green
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Andrews
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Newell
authors.forename: Francesca
authors.initials: F
authors.lastname: Fernandez-Enright
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D003071:Cognition / Q000502:physiology*; D005260:Female; D060005:Genotyping Techniques; D000072233:Homer Scaffolding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D012727:Sex Characteristics
chemical_list: D002352:Carrier Proteins; C539678:FRMPD4 protein, human; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins