Department of Medicine

Dr. Ravinesh A. Kumar, Ph.D.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Director of Research

Conte Center for Computational Systems Genomics

 of Neuropsychiatric Phenotypes

 

The University of Chicago

Institute for Genomics & Systems Biology

Knapp Center for Biomedical Discovery (KCBD)

Department of Medicine | Section of Genetic Medicine

900 E. 57^th  Street, KCBD 10160B | Chicago, IL 60637

Voice: 773-702-6799 | Fax: 773-834-2877 | Email: rakumar@uchicago.edu

Personal Website: http://home.uchicago.edu/~rakumar

 

 

 

 

 

 

 

 

Research Training

 

POSTDOCTORAL RESEARCH

Professor Conrad T. Gilliam (July 2010 - January 2012)

Professor William B. Dobyns  (January 2007 - July 2010)

 

1. Genetics of Autism Spectrum Disorders

Autism is one of the most heritable of all neuropsychiatric disorders and comprises the severe end of a group of autism spectrum disorders (ASD), which also include Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and Rett syndrome. Although there is firm evidence for a genetic basis for autism, only a few genes have been identified to date (Reviewed in Kumar and Christian, Current Neurology and Neuroscience Reports, 2009). To discover novel genes for ASD, we are using whole-genome DNA and RNA microarray approaches and high-throughput DNA sequencing. We have identified nearly 60 submicroscopic chromosomal rearrangements associated with autism (Christian et al, Biological Psychiatry, 2008). We and others have also demonstrated that 16p11.2 microdeletions and duplications are among the most frequent chromosomal abnormalities associated with autism, a discovery that represents one of the top ten scientific achievements in autism in 2008. We have also implicated 16p11.2 rearrangements in schizophrenia (McCarthy et al, Nature Genetics, 2009) and infantile seizure disorder (Bedoyan et al, AJMG Part A, In press). Our DNA sequencing studies have identified at least three candidate genes that may underlie risk for autism, including the seizure-related gene SEZ6L2 (Kumar et al, PLoS ONE, 2009) and the synaptic vesicle genes APBA2 (Babatz et al, Autism Research, 2009) and RIMS3 (Kumar et al, Journal of Medical Genetics, 2010).

 

2. Genetics of Cortical Malformations and Epilepsy

Human brain malformations, such as lissencephaly (smooth brain), microcephaly (small brain), and polymicrogyria (excessive number of small cortical folds), are rare childhood neurodevelopmental disorders that are frequently associated with mental retardation and epilepsy. The molecular bases for these disorders may involve abnormalities in neuronal migration, proliferation, or differentiation. To discover novel genes for human brain and cognitive development, we are using classical and emergent approaches that include linkage mapping, cytogenetics, molecular genetics, and copy number variant (CNV) analysis using microarray-based comparative genomic hybridization (aCGH) and SNP genotyping platforms. Our most recent work in this area implicates mutations in TUBA1A with wide spectrum lissencephaly, making this the first major gene associated with ’lissencephaly with cerebellar hypoplasia (LCH)’. (Kumar et al 2010).

 

3. Development of integrated bioinformatics platforms and computational networks-based disease models

A major challenge for biomedical research is discovering the genetic and pathophysiological mechanisms underlying heritable brain disorders. We propose to address these challenges by developing a publicly scalable and integrated systems biology platform that will allow prediction of pathways or networks of interacting genes that contribute to heritable neurodevelopmental disorders. Specifically, our platforms will support automated, as well as interactive expert-driven development, analysis and visualization of networks-based disease models. These models will provide a conceptual framework for systems-level exploration of complex genotype-phenotype relationships by combining the standard genetic linkage and association formalisms with whole-genome molecular-interaction data.

 

DOCTORAL RESEARCH: (January 2001– December 2006)

Dissertation: ‘Genetic and Genomic Studies of Mouse and Human NR2E1 in Cortical Disorders, Aggressive Behaviour and Psychiatric Disease’

The University of British Columbia, Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics (Vancouver, Canada)

Advisor:  Dr. Elizabeth M. Simpson.

As part of my graduate work, I demonstrated that ‘fierce’ mice, which are pathologically violent and display abnormal brain development, are deleted for a single nuclear receptor gene called Nr2e1 (Kumar et al, Genesis: The Journal of Genetics and Development, 2004). I also tested the hypothesis that NR2E1 underlies human brain and behavioral disorders. I used molecular, bioinformatic, and evolutionary genetic approaches to study NR2E1 in children with microcephaly (Kumar et al, Genes, Brain and Behavior, 2007), in children with microcephaly, microphthalmia, ectrodactyly, and prognathism (MMEP) (Kumar et al, BMC Medical Genetics, 2007), and in adults with bipolar disorder, schizophrenia, and aggressive behavior (Kumar et al, Am J Med Gen Neuropsychiatric Genetics, 2008). Together, these studies support the hypothesis that common and rare genetic variation at NR2E1 may underlie human brain and behavioral development and disease.

 

Significance: The identification and functional evaluation of genes that underlie severe brain malformations and autism will lead to a better understanding of the molecular bases of human brain development, social behavior, cognition, and language development. These discoveries will lead to improved clinical molecular diagnostics, genetic counseling, and therapeutic interventions to treat and manage neuropsychiatric and developmental disorders.

 

The Conte Center for Computational Systems Genomics of Neuropsychiatric Phenotypes is a cross-disciplinary and multi-institutional effort involving seven universities: The University of Chicago, Northwestern University, The University of Illinois at Chicago, Harvard University, Stanford University, Columbia University, and the University of Haifa in Israel. The overarching goal of the Center is to discover the genetic and environmental factors that underlie psychiatric disorders, including autism, schizophrenia, bipolar disorder, major depression, and anxiety disorder. Our team develops and applies drastically new mathematical and computational strategies to infer causal relationships among genetic variation, environment variables and psychiatric phenotypes by combining the statistical power of pre-existing genetics, pharmacogenomics, text-mining and clinical record databases. As Director of Research, I oversee the management, research, education & outreach, and major operations of this multi-million dollar project. I am also working on several research projects. Current projects include identifying the molecular basis of human brain connectivity using data generated from patients with severe abnormalities of the corpus callosum - the largest connective structure in the human brain. Other research interests include the characterization of the genetic and environmental structure of child and adolescent psychopathology, including conduct disorder, oppositional defiant disorder, hyperactivity-impulsivity, and obsessive-compulsive disorder. Together, these studies will lead to a better understanding of the genetic and non-genetic bases of mental health and illness.