RESUMO
CONTEXT: The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function. OBJECTIVE: To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls. DESIGN: Comparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples. SETTING: Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained. PARTICIPANTS: Patients with DSM-IV-diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality. MAIN OUTCOME MEASURES: In this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample. RESULTS: In the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened. CONCLUSIONS: In a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.
Assuntos
Transtornos Cognitivos/genética , Predisposição Genética para Doença/genética , Fatores de Transcrição Kruppel-Like/genética , Esquizofrenia/genética , Dedos de Zinco/genética , Adulto , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico , Feminino , Frequência do Gene , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha/etnologia , Humanos , Irlanda/etnologia , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/genética , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/genética , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , População Branca/genéticaRESUMO
CONTEXT: Human and animal studies have implicated the gene NOS1 in both cognition and schizophrenia susceptibility. OBJECTIVE: To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects. DESIGN: A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample. SETTING: Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained. PARTICIPANTS: Patients with DSM-IV-diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality. RESULTS: A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also. CONCLUSIONS: NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.
