title: The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up.
abstract: OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales.
authors.forename: James T R
authors.initials: JT
authors.lastname: Walters
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vásquez
authors.forename: April
authors.initials: A
authors.lastname: Hargreaves
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Russo
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.forename: Martine
authors.initials: M
authors.lastname: Hoogman
authors.forename: Andrea
authors.initials: A
authors.lastname: Da Costa
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Guillén
authors.initials: G
authors.lastname: Fernández
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Gary
authors.initials: G
authors.lastname: Donohoe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D003431:Cross-Cultural Comparison; D005500:Follow-Up Studies; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007494:Ireland; D008279:Magnetic Resonance Imaging; D008285:Major Histocompatibility Complex / Q000235:genetics*; D061212:Memory, Episodic; D008875:Middle Aged; D051579:Neurogranin / Q000235:genetics; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D012565:Schizophrenic Psychology; D055815:Young Adult
chemical_list: C496649:NRGN protein, human; D051579:Neurogranin