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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




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.


Education:
PhD
MD

Publications (Pulled from Harvard Catalyst Profiles):

1. White CC, Yang HS, Yu L, Chibnik LB, Dawe RJ, Yang J, Klein HU, Felsky D, Ramos-Miguel A, Arfanakis K, Honer WG, Sperling RA, Schneider JA, Bennett DA, De Jager PL. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med. 2017 Apr; 14(4):e1002287.

2. Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017 Apr 21; 356(6335).

3. Lim AS, Klein HU, Yu L, Chibnik LB, Ali S, Xu J, Bennett DA, De Jager PL. Diurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer's disease. Nat Commun. 2017 Apr 03; 8:14931.

4. Mathee A, De Jager P, Naidoo S, Naicker N. Lead poisoning in shooting-range workers in Gauteng Province, South Africa: Two case studies. S Afr Med J. 2017 Mar 29; 107(4):302-303.

5. Felsky D, Xu J, Chibnik LB, Schneider JA, Knight J, Kennedy JL, Bennett DA, De Jager PL, Voineskos AN. Genetic epistasis regulates amyloid deposition in resilient aging. Alzheimers Dement. 2017 Mar 17.

6. Xia Z, Steele SU, Bakshi A, Clarkson SR, White CC, Schindler MK, Nair G, Dewey BE, Price LR, Ohayon J, Chibnik LB, Cortese IC, De Jager PL, Reich DS. Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members. JAMA Neurol. 2017 Mar 01; 74(3):293-300.

7. Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, Carrell D, Cai Y, Fernandez MV, Budde J, Ma S, Saef B, Howells B, Huang KL, Bertelsen S, Fagan AM, Holtzman DM, Morris JC, Kim S, Saykin AJ, De Jager PL, Albert M, Moghekar A, O'Brien R, Riemenschneider M, Petersen RC, Blennow K, Zetterberg H, Minthon L, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Schellenberg G, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Peskind ER, Li G, Di Narzo AF, Kauwe JS, Goate AM, Cruchaga C. Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers. Acta Neuropathol. 2017 May; 133(5):839-856.

8. Chun S, Casparino A, Patsopoulos NA, Croteau-Chonka DC, Raby BA, De Jager PL, Sunyaev SR, Cotsapas C. Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types. Nat Genet. 2017 Apr; 49(4):600-605.

9. Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, Buxbaum JD, Byrd GS, Carrasquillo MM, Crane PK, Cruchaga C, De Jager P, Ertekin-Taner N, Evans D, Fallin MD, Foroud TM, Friedland RP, Goate AM, Graff-Radford NR, Hendrie H, Hall KS, Hamilton-Nelson KL, Inzelberg R, Kamboh MI, Kauwe JS, Kukull WA, Kunkle BW, Kuwano R, Larson EB, Logue MW, Manly JJ, Martin ER, Montine TJ, Mukherjee S, Naj A, Reiman EM, Reitz C, Sherva R, St George-Hyslop PH, Thornton T, Younkin SG, Vardarajan BN, Wang LS, Wendlund JR, Winslow AR, Haines J, Mayeux R, Pericak-Vance MA, Schellenberg G, Lunetta KL, Farrer LA. Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement. 2017 Feb 07.

10. Yu L, Lutz MW, Wilson RS, Burns DK, Roses AD, Saunders AM, Gaiteri C, De Jager PL, Barnes LL, Bennett DA. TOMM40'523 variant and cognitive decline in older persons with APOE e3/3 genotype. Neurology. 2017 Feb 14; 88(7):661-668.