Wednesday, 20 February 2013

Research: Imaging genetics

Gourraud PA, Sdika M, Khankhanian P, Henry RG, Beheshtian A, Matthews PM, Hauser SL, Oksenberg JR, Pelletier D, Baranzini SE. A genome-wide association study of brain lesion distribution in multiple sclerosis. Brain. 2013 Feb [Epub ahead of print]

Brain magnetic resonance imaging is widely used as a diagnostic and monitoring tool in multiple sclerosis and provides a non-invasive, sensitive and reproducible way to track the disease. Topological characteristics relating to the distribution and shape of lesions are recognized as important neuroradiological markers in the diagnosis of multiple sclerosis, although these have been much less well characterized quantitatively than have traditional measures such as T(2) hyperintense or T(1) hypointense lesion volumes. 

Here, we used voxel-level 3 T magnetic resonance imaging T(1)-weighted scans to reconstruct the 3D topology of lesions in 284 subjects with multiple sclerosis and tested whether this is a heritable phenotype. To this end, we extracted the genotypes from a published genome-wide association study on these same individuals and searched for genetic associations with lesion load, shape and topological distribution. Lesion probability maps were created to identify frequently affected areas and to assess the overall distribution of T(1) lesions in the subject population as a whole. We then developed an original algorithm to cluster adjacent lesional voxels (cluxels) in each subject and tested whether cluxel topology was significantly associated with any single-nucleotide polymorphism in our data set. To focus on patterns of lesion distribution, we computed the first 10 principal components. Although principal component 1 correlated with lesion load, none of the remaining orthogonal components correlated with any other known variable. We then conducted genome-wide association studies on each of these and found 31 significant associations (false discovery rate <0.01) with principal component 8, which represents a mode of variation of lesion topology in the population. The majority of the loci can be linked to genes related to immune cell function and to myelin and neural growth; some (SYK, MYT1L, TRAPPC9, SLITKR6 and RIC3) have been previously associated with the distribution of white matter lesions in multiple sclerosis. Finally, we used a bioinformatics approach to identify a network of 48 interacting proteins showing genetic associations (P < 0.01) with lesional topology in multiple sclerosis. This network also contains proteins expressed in immune cells and is enriched in molecules expressed in the central nervous system that contribute to neural development and regeneration. Our results show how quantitative traits derived from brain magnetic resonance images of patients with multiple sclerosis can be used as dependent variables in a genome-wide association study. With the widespread availability of powerful computing and the availability of genotyped populations, integration of imaging and genetic data sets is likely to become a mainstream tool for understanding the complex biological processes of multiple sclerosis and other brain disorders.
Genetic analysis of MS has identified over 50 genes that are associated with susceptibility to MS, this study looks at imaging data and asks the question of whether the location of lesions could be influenced by the genetic make up of MSers. They looked at the pattern of lesions and then compared this to the genes expressed. They found some difference in lesion distribution and genetics. These genes were related to immune function just like other MS-susceptibility genes Some of these can be grouped in a network of interacting proteins. Genetics is a powerful tool and the power of genetic analysis is helped by having good clinical data to determined if subgroups can be identified for genetic analysis studies

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