Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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In the Lab:
Badri N. Vardarajan, PhD, MS

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Badri Vardarajan, PhD, MSBadri N. Vardarajan, PhD, MS

Recently-developed techniques in DNA sequencing are creating a wealth of data for researchers to analyze. In my research, which focuses on understanding the genetic and genomic mechanisms behind neuro-degenerative diseases, I use advanced computational approaches to identify and interpret relevant signals among all this biological data.

In collaboration with Dr. Richard Mayeux and the Laboratory for Genetic Epidemiology, I work with data from the Caribbean Hispanic population of Northern Manhattan and large families from the Dominican Republic, who have a high rate of Alzheimer's disease (AD). We have generated multi-omics datasets including whole genome, whole exome, and RNA sequencing in this population.

Figure 1. Missense damaging mutation rs202178565 in EPHA1 (ephrin type‐A receptor 1). This mutation was not found in any external controls. Import ID = internal subject ID; APOE_AB = APOE ε4 status;

Most of my research involves hunting for rare variants that may be tied to AD. For example, using the whole exome sequencing technology, we identified a rare mutation in the EPHA1 gene (Figure 1) segregating with disease status in a multiplex Caribbean Hispanic family. This effect of the mutation on the resulting protein product was tested in the laboratory of Dr. Roger Lefort. They determined that the proline to leucine substitution (EphA1P460L) results in auto-phosphorylation and auto-activation of the protein, suggesting enhanced EphA1 signaling. We are now investigating whether EphA1 upregulation triggers one or more downstream pathways leading to AD changes in the brain.

In another study, we are trying to find mutations in the genome that protect some individuals who are otherwise at high risk of AD. Presence of the APOEε4 allele is the biggest confirmed genetic risk factor for Late-Onset Alzheimer's Disease (LOAD) in white, non-Hispanic populations, but the associated risks observed in African-Americans and Hispanics are somewhat lower. However, in virtually every population, homozygosity for the APOEε4 allele is associated with increased risk and nearly complete penetrance. We are studying whole genome sequence data on high risk elderly individuals that carry two copies of the APOE e4 allele but are free of AD. These individuals are from Caribbean Hispanic families with multiple LOAD patients, and at least one unaffected individual who is APOEε4 homozygous, with age greater than average age-at-onset in the family.

I am also interested in developing algorithms that can solve complex genomic problems. I am developing methods that study interactions among genes, as standard approaches are limited in the ability to analyze computationally intractable numbers of interactions. Currently, I am exploring the application of game theory based techniques (frequently used in Economics) to problems in large-scale gene interaction analysis. This allows for the identification of collaborative or compensatory interactions among genes.

Badri N. Vardarajan, PhD, MS
Assistant Professor of Bioinformatics
bnv2103@cumc.columbia.edu





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