title: Genetic vulnerability to psychosis and cortical function: epistatic effects between DAAO and G72.
abstract: Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p < 0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King’s College London, De Crespigny Park, SE5 8AF UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mechelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Fusar-Poli
authors.forename: Diana
authors.initials: D
authors.lastname: Prata
authors.forename: Sergio Alessandro
authors.initials: SA
authors.lastname: Papagni
authors.forename: Stefania
authors.initials: S
authors.lastname: Tognin
authors.forename: Joseph
authors.initials: J
authors.lastname: Kambeitz
authors.forename: Cynthia
authors.initials: C
authors.lastname: Fu
authors.forename: Marco
authors.initials: M
authors.lastname: Picchioni
authors.forename: Muriel
authors.initials: M
authors.lastname: Walshe
authors.forename: Timothea
authors.initials: T
authors.lastname: Toulopoulou
authors.forename: Elvira
authors.initials: E
authors.lastname: Bramon
authors.forename: Robin
authors.initials: R
authors.lastname: Murray
authors.forename: Philip
authors.initials: P
authors.lastname: McGuire
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002540:Cerebral Cortex / Q000502:physiology*; D003605:D-Amino-Acid Oxidase / Q000096:biosynthesis / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics / Q000523:psychology; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; C417983:DAO protein, human; D003605:D-Amino-Acid Oxidase