Front. Psychiatry, 19 April 2012 |

Connectomic intermediate phenotypes for psychiatric disorders

  • 1 Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Carlton South, VIC, Australia
  • 2 Brain Mapping Unit, Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, UK
  • 3 GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke’s Hospital, Cambridge, UK

Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome.

Keywords: endophenotype, schizophrenia, depression, Alzheimer’s disease, anxiety, complex, graph analysis, default mode

Citation: Fornito A and Bullmore ET (2012) Connectomic intermediate phenotypes for psychiatric disorders. Front. Psychiatry 3:32. doi: 10.3389/fpsyt.2012.00032

Received: 25 November 2011; Accepted: 23 March 2012;
Published online: 19 April 2012.

Edited by:

Ben Harrison, The University of Melbourne, Australia

Reviewed by:

Lukas Pezawas, Medical University of Vienna, Austria
Jingyu Liu, University of New Mexico, Mexico

Copyright: © 2012 Fornito and Bullmore. 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: Alex Fornito, Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Levels 2 and 3, 161 Barry Street, Carlton South 3053, VIC, Australia. e-mail: