title: Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk.
abstract: Evidence suggests that there is shared genetic aetiology across the major psychiatric disorders conferred by additive effects of many common variants. Measuring their joint effects on brain function may identify common neural risk mechanisms. We investigated the effects of a cross-disorder polygenic risk score (PGRS), based on additive effects of genetic susceptibility to the five major psychiatric disorders, on brain activation during performance of a language-based executive task. We examined this relationship in healthy individuals with (n=82) and without (n=57) a family history of bipolar disorder to determine whether this effect was additive or interactive dependent on the presence of family history. We demonstrate a significant interaction for polygenic loading×group in left lateral frontal cortex (BA9, BA6). Further examination indicated that this was driven by a significant positive correlation in those without a family history (i.e. healthy unrelated volunteers), with no significant relationships in the familial group. We then examined the effect of the individual diagnoses contributing to the PGRS to determine evidence of disorder-specificity. We found a significant association with the schizophrenia polygenic score only, with no other significant relationships. These findings indicate differences in left lateral frontal brain activation in association with increased cross-disorder PGRS in individuals without a family history of psychiatric illness. Lack of effects in the familial group may reflect epistatic effects, shared environmental influences or effects not captured by the PGRS. The specific relationship with loading for schizophrenia is notably consistent with frontal cortical inefficiency as a circumscribed phenotype of psychotic disorders.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK. Electronic address: heather.whalley@ed.ac.uk.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Whalley
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Hall
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: Liana
authors.initials: L
authors.lastname: Romaniuk
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: Alix
authors.initials: A
authors.lastname: Macdonald
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lawrie
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: Jessika E
authors.initials: JE
authors.lastname: Sussmann
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000503:physiopathology; D001321:Autistic Disorder / Q000235:genetics / Q000503:physiopathology; D001714:Bipolar Disorder / Q000235:genetics / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000235:genetics / Q000503:physiopathology; D005190:Family; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D007839:Functional Laterality; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D007406:Interview, Psychological; D008297:Male; D020412:Multifactorial Inheritance; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D055815:Young Adult
keywords: Frontal cortex; Polygenic; Schizophrenia; fMRI