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Influence of NOS1 on Verbal Intelligence and Working Memory in Both Patients With Schizophrenia and Healthy Control Subjects
Gary Donohoe, DClinPsych, PhD;
James Walters, MRCPsych, BM;
Derek W. Morris, PhD;
Emma M. Quinn, MSc;
Róisín Judge, BA;
Nadine Norton, PhD;
Ina Giegling, PhD;
Annette M. Hartmann, PhD;
Hans-Jürgen Möller, MD;
Pierandrea Muglia, MD;
Hywel Williams, PhD;
Valentina Moskvina, PhD;
Rosemary Peel, MSc;
Therese O’Donoghue, MSc;
Michael J. Owen, FRCPsych, PhD;
Michael C. O’Donovan, FRCPsych, PhD;
Michael Gill, MRCPsych, MD;
Dan Rujescu, MD;
Aiden Corvin, MRCPsych, PhD
Arch Gen Psychiatry. 2009;66(10):1045-1054.
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.
Author Affiliations: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine (Drs Donohoe, Morris, Gill, and Corvin and Mss Quinn, Judge, Peel, and O’Donoghue) and Trinity Institute of Neuroscience (Drs Donohoe, Gill, and Corvin and Ms O’Donoghue), Trinity College Dublin, Dublin, Ireland; Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, Wales (Drs Walters, Norton, Williams, Moskvina, Owen, and O’Donovan); Division of Molecular and Clinical Neurobiology, Department of Psychiatry (Drs Giegling, Hartmann, and Rujescu) and Department of Psychiatry (Dr Möller), Ludwig-Maximilians-Universität, Munich, Germany; and Medical Genetics, Research & Development, GlaxoSmithKline, Verona, Italy (Dr Muglia).
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