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Zoran Brkanac MD

Associate Professor

zbrkanac@u.washington.edu
Phone: (206) 543-9573
Fax: (206) 543-9520

Site: UW Medical Center
Health Sciences Building
1959 NE Pacific Street
Box 356560
Seattle, WA 98195
Link to CV
Link to Website


Board Certification
American Board of Psychiatry and Neurology
Child and Adolescent Subspecialty

Bio

The Brkanac laboratory focuses on family based approaches for analyzing human genetic variation in order to identify rare highly penetrant variants responsible for severe neuropsychiatric and neurodegenerative disorders such as autism, schizophrenia and Alzheimer disease. To identify causal variants we are using whole exome sequencing of affected cases from large pedigrees with multiple affected family members. To replicate causality for newly discovered mutations we are using next-generation sequencing and case-control gene based study design and following up with functional studies.

Autism is one of the most heritable neurogenetic disorders, with a genetic basis well established through family and twin epidemiological studies. Genome-wide association studies have not found strong evidence for the contribution of common variants, and linkage studies indicate the presence of multiple loci, each of which contributes negligibly to the genetic variants on a population level. The goal of our research is to apply a novel analytic approach to identify families from existing UW and NIH collections where inheritance is most parsimonious with single gene transmission and to apply Next generation sequencing to identify the genes that are responsible for the phenotype. We have identified large extended families and are applying population genetics methods to identify cryptically related small families where the likelihood of dominant and recessive inheritance is increased. We are capitalizing on newly available methods for whole exome sequencing to identify variants that might be causal. Lastly, the candidate genes identified will be evaluated for association with autism in a large case-control study. The understanding of the genetics of autism will facilitate early interventions by enabling presymptomatic diagnosis, implicate additional biological pathways involved in autism and increase the number of targets for causative treatments. In addition, similar approaches might be applicable for gene discovery in other neuropsychiatric disorders such as schizophrenia.

Alzheimer disease (AD) has a strong genetic basis and additional Mendelian genes remain to be identified. Mutations in the APP, PSEN1 or PSEN2 genes are involved in minority of AD families that are characterized with early disease onset. Large genome-wide association studies have not found strong evidence for the contribution of common variants besides the APOE gene. Although many families with pedigrees suggestive of autosomal dominant inheritance have been described and linkage studies have found evidence for multiple contributing loci, no new genes have been identified in the last 20 years. Similar to Autism project, the goal of our research in AD is to apply novel analytic approaches to identify families in which AD is likely to have a single gene etiology and to utilize next generation sequencing technologies to detect these genes. We have identified large pedigrees where single genes are likely to be causal in existing well-characterized UW, NIA and NIMH AD collections. In addition to identifying large pedigrees, we are applying population genetics approaches to detect families that share a common ancestor and where the same genetic variant might be causal. To establish association of identified candidate genes with AD we will perform large gene-based mutational load case-control studies. The identification of novel AD genes would be a significant step towards an increased understanding of the genetic architecture of AD.







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