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James T. R. Walters, MRCPsych, BM; Aiden Corvin, MRCPsych, PhD; Michael J. Owen, FRCPsych; Hywel Williams, PhD; Milan Dragovic, PhD; Emma M. Quinn, MSc; Róisín Judge, BA; Daniel J. Smith, MD; Nadine Norton, PhD; Ina Giegling, PhD; Annette M. Hartmann, PhD; Hans-Jürgen Möller, MD; Pierandrea Muglia, MD; Valentina Moskvina, PhD; Sarah Dwyer, PhD; Therese O’Donoghue, MSc; Bharti Morar, PhD; Matthew Cooper, MSc; David Chandler, PhD; Assen Jablensky, MD, PhD; Michael Gill, MRCPsych, MD, PhD; Luba Kaladjieva, MD, PhD; Derek W. Morris, PhD; Michael C. O’Donovan, FRCPsych, PhD; Dan Rujescu, MD; Gary Donohoe, DClinPsych, PhD

Arch Gen Psychiatry. 2010;67(7):692-700. doi:10.1001/archgenpsychiatry.2010.81

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.

Author Affiliations: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, Wales (Drs Walters, Owen, Williams, Smith, Norton, Moskvina, Dwyer, and O’Donovan); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine (Drs Corvin, Gill, Morris, and Donohoe; Mss Quinn, Judge, and O’Donoghue), and Trinity Institute of Neuroscience (Drs Corvin, Gill, and Donohoe and Ms O’Donoghue), Trinity College, Dublin, Ireland; Molecular and Clinical Neurobiology (Drs Giegling, Hartmann, and Rujescu) and Department of Psychiatry (Drs Giegling, Hartmann, Möller, and Rujescu), Ludwig-Maximilians-University, Munich, Germany; Medical Genetics, GlaxoSmithKline R&D, Verona, Italy (Dr Muglia); and Centre for Medical Research/Western Australian Institute for Medical Research (Drs Morar, Chandler, and Kaladjieva and Mr Cooper), Centre for Clinical Research in Neuropsychiatry (Drs Dragovic and Jablensky), and Centre for Genetic Epidemiology and Biostatistics (Mr Cooper), The University of Western Australia, Perth.

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