Imaging genomics

Abstract

The recent completion of a working draft of the human genome sequence promises to provide unprecedented opportunities to explore the genetic basis of individual differences in complex behaviours and vulnerability to neuropsychiatric illness. Functional neuroimaging, because of its unique ability to assay information processing at the level of brain within individuals, provides a powerful approach to such functional genomics. Recent fMRI studies have established important physio- logical links between functional genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and anxiety disorders. Importantly, all of these biological relation- ships have been revealed in relatively small samples of healthy volunteers and in the absence of observable differences at the level of behaviour, underscoring the power of a direct assay of brain physiology like fMRI in exploring the functional impact of genetic variation. Identifying the biological mechanisms that contribute to complex cognitive and emotional behaviours is paramount to our understanding of how individual differences in these behaviours emerge and how such differences may confer vulnerability to psychiatric disease. Advances in both molecular genetics and non-invasive functional neuroimaging have begun to provide the tools necessary to explore these as well as other behaviourally relevant biological mechanisms. With completion of a rough draft of the reference human genome sequence 1,2 , a major effort is underway to identify common variations in this sequence that impact on gene function (i.e. functional polymorphisms) and subsequently to understand how such functional variations alter human biology. Since approximately 70% of all genes are expressed in brain, many of these functional polymorphisms will effect how the brain processes information. Functional neuroimaging (i.e. PET, fMRI, EEG/MEG), because of its capacity to assay within individuals information processing in discreet brain circuits, has unique potential as a tool for characterizing functional genomics in brain. In this review, we: (i) describe the conceptual basis for, and potential of, this synthetic approach, referred to here as imaging genomics; (ii) propose several