Abstract
BackgroundSchizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. However, the biological mechanisms underpinning the different symptom clusters remain undefined. The rs1344706 single nucleotide polymorphism within ZNF804A was among the first genetic variants found to be associated with schizophrenia. Previously, neuroimaging and cognitive studies have revealed several associations between rs1344706 and brain structure and function. The aim of this study is to use a recall-by-genotype (RBG) design to investigate the biological basis for the association of ZNF804A variants with schizophrenia. A RBG study, implemented in a population cohort, will be used to evaluate the impact of genetic variation at rs1344706 on sleep neurophysiology and procedural memory consolidation in healthy participants.Methods/DesignParticipants will be recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) on the basis of genotype at rs1344706 (n = 24). Each participant will be asked to take part in two nights of in-depth sleep monitoring (polysomnography) allowing collection of neurophysiological sleep data in a manner not amenable to large-scale study. Sleep questionnaires will be used to assess general sleep quality and subjective sleep experience after each in-house recording. A motor sequencing task (MST) will be performed before and after the second night of polysomnography. In order to gather additional data about habitual sleep behaviour participants will be asked to wear a wrist worn activity monitor (actiwatch) and complete a sleep diary for two weeks.DiscussionThis study will explore the biological function of ZNF804A genotype (rs1344706) in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning. Using a RBG approach will enable us to collect precise and detailed phenotypic data whilst achieving an informative biological gradient. It would not be feasible to collect such data in the large sample sizes that would be required under a random sampling scheme. By dissecting the role of individual variants associated with schizophrenia in this way, we can begin to unravel the complex genetic mechanisms of psychiatric disorders and pave the way for future development of novel therapeutic approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0244-4) contains supplementary material, which is available to authorized users.
Highlights
Schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis
This study will explore the biological function of ZNF804A genotype in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning
This finding has since been replicated in a number of other Genome wide association studies (GWAS) [1, 3,4,5] including a fine-mapping study that failed to detect any genetic variants within the ZNF804A locus that were more strongly associated with schizophrenia than rs1344706, which in this analysis had an OR for schizophrenia of 1.10 [1.07 – 1.14] [6]
Summary
Schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. In a GWAS of 479 patients with schizophrenia and 2937 controls (with replication of associated variants in a further 16,726 subjects) the strongest evidence for association was shown for rs1344706 (odds ratio [OR] 1.12, p = 1.95 × 10−7), a single nucleotide polymorphism (SNP) within the ZNF804A gene [2]. This finding has since been replicated in a number of other GWAS [1, 3,4,5] including a fine-mapping study that failed to detect any genetic variants within the ZNF804A locus that were more strongly associated with schizophrenia than rs1344706, which in this analysis had an OR for schizophrenia of 1.10 [1.07 – 1.14] [6]. Sleep disturbances have long been described in schizophrenia [19, 20] with studies consistently reporting altered sleep architecture where patients show increased sleep latency (time taken to fall asleep), decreased total sleep time and other altered sleep variables both on neuroleptic treatment and in the absence of medication [21, 22]
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