Dr. Christopher D. Anderson is a Neurocritical Care and Stroke Neurologist at Massachusetts General Hospital (MGH), whose career goal is to develop an independent research program as a computational genetic biologist capable of using advanced bioinformatic and statistical methods to obtain maximal scientific yield from large-scale genetic and genomic studies, with the aim of returning meaningful and actionable results that improve understanding of cerebral small vessel disease (CSVD) and identify novel targets for therapeutic development. As a first step toward this goal, he plans to use data from genome-wide studies to examine genetic variants within biological networks associated with lipid levels to uncover the mechanisms by which lipids influence CSVD. This proposal addresses a key area of controversy, as current data suggest conflicting roles for lipid levels depending on the particular form of cerebrovascular disease under study. Cerebral small vessel disease, which underlies intracerebral hemorrhage (ICH), radiographic white matter disease, and cerebral microbleeds, may be worsened by reduced lipid levels, while overall ischemic stroke risk appears to benefit from this strategy. Dr. Anderson has established an early career track record in the analysis of common genetic variant data to identify new associations in ischemic stroke, ICH, and Alzheimer Disease, and his preliminary data demonstrate the feasibility of biologically-informed genetic analysis in cerebrovascular disease. His career plan leverages the extensive resources and exceptional environments of Massachusetts General Hospital and the Broad Institute, under the mentorship of Dr. Jonathan Rosand and co-mentorship of Drs. Sekar Kathiresan, Mark Daly, and Ona Wu. In this Career Development Award, Dr. Anderson proposes to: 1) discover the impact of common genetic variants known to affect lipid levels on the risk of ICH and severity of neuroimaging manifestations of CSVD, 2) determine the impact of rare genetic variants in gene networks with a role in lipid levels on risk of ICH and severity of these same neuroimaging measures, and 3) use advanced bioinformatics tools to construct novel gene networks associated with lipid levels, and test these networks for association with ICH and neuroimaging measures to uncover new biological targets. The proposed study will employ genetic and informatic tools to demonstrate the direction and magnitude of effect that lipids exert on CSVD. These analyses offer the promise of yielding novel targets for drug development, and will further our understanding of the potential risks of lipid modifying therapy. Dr. Anderson has assembled a team with expertise in complex disease genetics, lipid epidemiology, neuroimaging, and advanced bioinformatics techniques that will ensure that this proposal maximally leverages the data generated. This Award will provide Dr. Anderson with the skills to evolve into an independent clinician-scientist with a computational research program that can nimbly analyze large genetic datasets to derive results that are highly relevant to the prevention and treatment of cerebrovascular disease in his clinical patient population.

Public Health Relevance

While advances in medical management have led to improvements in prevention and treatment, intracerebral hemorrhage occurs in over 70,000 people in the U.S. each year, half of whom die of the disease. Related manifestations of cerebral small vessel disease include age-related cognitive impairment, gait disorders, and late-life depression. Dr. Anderson's proposed career development plan and research strategy hold great promise in improving our understanding of the precise role cholesterol plays in the onset and progression of intracerebral hemorrhage and cerebral small vessel disease, which is a crucial step towards the development of more effective treatment strategies for treatment and prevention of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Gwinn, Katrina
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Massachusetts General Hospital
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Morotti, Andrea; Marini, Sandro; Jessel, Michael J et al. (2017) Lymphopenia, Infectious Complications, and Outcome in Spontaneous Intracerebral Hemorrhage. Neurocrit Care 26:160-166
Phuah, Chia-Ling; Dave, Tushar; Malik, Rainer et al. (2017) Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke. Brain 140:2663-2672
Marini, Sandro; Morotti, Andrea; Ayres, Alison M et al. (2017) Sex differences in intracerebral hemorrhage expansion and mortality. J Neurol Sci 379:112-116
Marini, Sandro; Morotti, Andrea; Lena, Umme K et al. (2017) Men Experience Higher Risk of Pneumonia and Death After Intracerebral Hemorrhage. Neurocrit Care :
(2017) 19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium. Neurol Genet 3:S2-S11
Anderson, Christopher D; Falcone, Guido J; Phuah, Chia-Ling et al. (2016) Genetic variants in CETP increase risk of intracerebral hemorrhage. Ann Neurol 80:730-740
Phuah, Chia-Ling; Raffeld, Miriam R; Ayres, Alison M et al. (2016) APOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage. Neurol Genet 2:e81
Morotti, Andrea; Jessel, Michael J; Brouwers, H Bart et al. (2016) CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage. Neurocrit Care 25:79-85
Morotti, Andrea; Charidimou, Andreas; Phuah, Chia-Ling et al. (2016) Association Between Serum Calcium Level and Extent of Bleeding in Patients With Intracerebral Hemorrhage. JAMA Neurol 73:1285-1290
Traylor, Matthew; Anderson, Christopher D; Hurford, Robert et al. (2016) Oxidative phosphorylation and lacunar stroke: Genome-wide enrichment analysis of common variants. Neurology 86:141-5

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