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Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype–Based Approach

Lancaster, Thomas M.; Dimitriadis, Stavros L.; Tansey, Katherine E.; Perry, Gavin; Ihssen, Niklas; Jones, Derek K.; Singh, Krish D.; Holmans, Peter; Pocklington, Andrew; Davey Smith, George; Zammit, Stan; Hall, Jeremy; O’Donovan, Michael C.; Owen, Michael J.; Linden, David E.

Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype–Based Approach Thumbnail


Thomas M. Lancaster

Stavros L. Dimitriadis

Katherine E. Tansey

Gavin Perry

Derek K. Jones

Krish D. Singh

Peter Holmans

Andrew Pocklington

George Davey Smith

Stan Zammit

Jeremy Hall

Michael C. O’Donovan

Michael J. Owen

David E. Linden


Risk profile scores (RPS) derived from genome-wide association studies (GWAS) explain a considerable amount of susceptibility for schizophrenia (SCZ). However, little is known about how common genetic risk factors for SCZ influence the structure and function of the human brain, largely due to the constraints of imaging sample sizes. In the current study, we use a novel recall-by-genotype (RbG) methodological approach, where we sample young adults from a population cohort (Avon Longitudinal Study of Parents and Children: N genotyped = 8365) based on their SCZ-RPS. We compared 197 healthy individuals at extremes of low (N = 99) or high (N = 98) SCZ-RPS with behavioral tests, and structural and functional magnetic resonance imaging (fMRI). We first provide methodological details that will inform the design of future RbG studies for common SCZ genetic risk. We further provide an between group analysis of the RbG individuals (low vs high SCZ-RPS) who underwent structural neuroimaging data (T1—weighted scans) and fMRI data during a reversal learning task. While we found little evidence for morphometric differences between the low and high SCZ-RPS groups, we observed an impact of SCZ-RPS on blood oxygen level-dependent (BOLD) signal during reward processing in the ventral striatum (PFWE-VS-CORRECTED = .037), a previously investigated broader reward-related network (PFWE-ROIS-CORRECTED = .008), and across the whole brain (PFWE-WHOLE-BRAIN-CORRECTED = .013). We also describe the study strategy and discuss specific challenges of RbG for SCZ risk (such as SCZ-RPS related homoscedasticity). This study will help to elucidate the behavioral and imaging phenotypes that are associated with SCZ genetic risk.


Lancaster, T. M., Dimitriadis, S. L., Tansey, K. E., Perry, G., Ihssen, N., Jones, D. K., …Linden, D. E. (2019). Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype–Based Approach. Schizophrenia Bulletin: The Journal of Psychoses and Related Disorders, 45(2), 405-414.

Journal Article Type Article
Acceptance Date Mar 3, 2018
Online Publication Date Mar 28, 2018
Publication Date Mar 7, 2019
Deposit Date Apr 20, 2018
Publicly Available Date Apr 23, 2018
Journal Schizophrenia Bulletin
Print ISSN 0586-7614
Electronic ISSN 1745-1701
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 45
Issue 2
Pages 405-414


Published Journal Article (Advance online version) (795 Kb)

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Copyright Statement
Advance online version © The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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