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Philip Laurence De Jager, MD, PhD
Associate Neurologist, Brigham and Women's Hospital
Associate Professor of Neurology, Harvard Medical School

Brigham and Women's Hospital
Department of Neurology
75 Francis Street
Boston, MA 02115

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Research Narrative:

My research focuses on understanding the role of human genetic variation in neuroimmunologic function and neurologic disease, with a particular interest in the pathophysiology and treatment of an inflammatory disease of the central nervous system, multiple sclerosis (MS) as well as in the understanding of cognitive decline in healthy, aging individuals. Specifically, in MS, I am (1) using genome-wide association testing methods to find susceptibility loci and disease-modifying loci for MS, (2) pursuing the functional characterization of susceptibility alleles that we have recently discovered, (3) refining a gene expression signature for MS, and (4) using association mapping techniques to discover genetic determinants of MRI and neuropsychologic phenotypes in MS and healthy individuals. In relation to cognitive decline associated with aging, we are using the same techniques to explore the human genome for determinants of (1) the rate at which individuals lose cognitive function and (2) the extent Alzheimer’s disease-related neuropathology accumulated by aging individuals at the time of death.

In preparation for our MS studies, I have established a new DNA sample collection with the support of the MS Center; we have collected over 3000 subjects from the MS Center in the past three years. This partnership with the MS Center has been very fruitful, with over 2000 subjects with MS being recruited; these individuals have rich clinical phenotypes of disease course, severity, and response to treatment documented in the MS Center clinical database as well as serial MRIs at BWH with volumetric measurements such as lesion load and brain parenchymal fraction. We have published both an initial genome-wide association scan for MS susceptibility (NEJM 2007) as well as a subsequent meta-analysis of MS geneome scans (Nat Genet 2009) that report the discovery of multiple susceptibility loci. We are now beginning to explore the relationship of our clinical and radiographic phenotypes to genetic variation. Ultimately, we hope to develop diagnostic and prognostic algorithms for us in the clinic.

To explore the function of genetic variation associated with human disease, I created the PhenoGenetic Project, a resource that provides fresh blood samples from 1000 individuals based on their genotype or other characteristics. Our current work focuses on the effect of MS related genetic variation in serum analytes and the characteristics of Natural Killer cells, a cell population that we have demonstrated to be abnormal in MS.

In the field of cognitive decline, we are currently analyzing genome-wide association data in relation to two phenotypes: (1) a measure of Alzheimer’s disease-related pathology gathered from over 600 autopsied subjects and (2) longitudinal neuropsychological data that documents each individual’s trajectory of cognitive decline in over 2000 subjects. A profile of the DNA methylome in several brain regions of over 1000 of these subjects is also under way.

My research interest therefore lies in human genetics and neurology, with a particular interest in MS and neurodegeneration. Human genetics and genomics, computational methods and cellular immunology are some of the techniques that we are using today. This selection of method will doubtlessly evolve as we continue to explore the function of the genetic variation that we identify.