Front. Psychiatry, 09 March 2012 |

The effects of psychosis risk variants on brain connectivity: a review

Omar Mothersill1,2†, Sinead Kelly1,2†, Emma Jane Rose1,2 and Gary Donohoe1,2*
  • 1 Neuropsychiatric Genetics Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
  • 2 Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland

In light of observed changes in connectivity in schizophrenia and the highly heritable nature of the disease, neural connectivity may serve as an important intermediate phenotype for schizophrenia. However, how individual variants confer altered connectivity and which measure of brain connectivity is more proximal to the underlying genetic architecture (i.e., functional or structural) has not been well delineated. In this review we consider these issues and the relative sensitivity of imaging methodologies to schizophrenia-related changes in connectivity. We searched PubMed for studies considering schizophrenia risk genes AND functional or structural connectivity. Where data was available, summary statistics were used to determine an estimate of effect size (i.e., Cohen’s d). A random-effects meta-analysis was used to consider (1) the largest effect and (2) all significant effects between functional and structural studies. Schizophrenia risk variants involved in neurotransmission, neurodevelopment and myelin function were found to be associated with altered neural connectivity. On average, schizophrenia risk genes had a large effect on functional (mean d = 0.76) and structural connectivity (mean d = 1.04). The examination of the largest effect size indicated that the outcomes of functional and structural studies were comparable (Q = 2.17, p > 0.05). Conversely, consideration of effect size estimates for all significant effects suggest that reported effect sizes in structural connectivity studies were more variable than in functional connectivity studies, and that there was a significant lack of homogeneity across the modalities (Q = 6.928, p = 0.008). Given the more variable profile of effect sizes associated with structural connectivity, these data may suggest that structural imaging methods are more sensitive to a wider range of effects, as opposed to functional studies which may only be able to determine large effects. These conclusions are limited by methodological considerations, and require further investigation involving larger samples, multiple genes, and novel analysis techniques for confirmation.

Keywords: schizophrenia, functional connectivity, structural connectivity, genotype, effect size

Citation: Mothersill O, Kelly S, Rose EJ and Donohoe G (2012) The effects of psychosis risk variants on brain connectivity: a review. Front. Psychiatry 3:18. doi: 10.3389/fpsyt.2012.00018

Received: 02 December 2011; Accepted: 22 February 2012;
Published online: 09 March 2012.

Edited by:

Daniela Tropea, Trinity College Dublin, Ireland

Reviewed by:

Mikhail Pletnikov, Johns Hopkins University, USA
Andrew M. McIntosh, The University of Edinburgh, UK

Copyright: © 2012 Mothersill, Kelly, Rose and Donohoe. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

*Correspondence: Gary Donohoe, Associate Professor of Clinical Psychology and Neuropsychology, Neuropsychiatric Genetics Group, Department of Psychiatry, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’ Hospital, Dublin 8, Ireland. e-mail:

Omar Mothersill and Sinead Kelly have contributed equally to this work.