OHSU

Genetics and Epigenetics

Lead Investigators. The bulk of work in this area entails advanced bioinformatics work to examine large scale genetic data, spearheaded by Beth Wilmot, Ph.D.

Funding. This work is supported by NIMH Grant MH08665405 (PI: Joel Nigg, Ph.D.) as well as by philanthropic gifts to OHSU's ADHD program through the Department of Psychiatry.

OHSU Co-investigators and Consultants: Joel Nigg, Ph.D., Shannon McWeeney, Ph.D., Mitchell Turker, Ph.D., Lucia Carbone, Ph.D., Chris Harrington, Ph.D.

Outside OHSU Co-Investigators and Consultants. Steve Faraone, Ph.D., SUNY Buffalo, Jonathan Mill, Ph.D., Cambridge and Exeter Universities, England; Kjersti Aagard, M.D., Ph.D., Baylor University; Rebecca Fry, Ph.D., University of North Carolina, Moshe Szyf, Ph.D., McGill University, Canada; Benjamin Neale, Ph.D., Harvard/MIT Broad Institute, Alex Burt, Ph.D., Michigan State University, Kelly Klump, Ph.D., Michigan State University.

Aims. This arm of the ADHD program has two principal aims. The first principal aim is to link whole genome data, which examines thousands of probes across the genome, in relation to consolidated gene sets that can enhance overall prediction of ADHD. In turn, these gene findings will then be related to MRI brain imaging findings from the Brain imaging arm of the program, to identify unique ADHD biotypes. This work is done in two data groups. The first is a multi-site collection of thousands of DNA samples of ADHD and non-ADHD children assembled under the auspices of the worldwide Psychiatric Genetics Consortium. We carry out this work with the assistance and collaboration of Dr. Faraone and Dr. Neale. The second is the large cohort of 600 children being followed for the primary ADHD Longitudinal Study. These children also provide DNA samples. This cohort is supplemented by additional children from the Portland area who are not in the longitudinal study but participate in the genetic study.

The second principal aim is to identify unique epigenetic signatures that might serve as clinical biomarkers of ADHD. Here we receive critical consultative support from Dr. Mill, Dr. Fry, and others who provide intellectual support as noted. This work is done by examining marks known as DNA methylation that are observed on DNA samples. These are analyzed across the entire genome, again using thousands of probes, or else by targeted sequencing of key regions of the genome. This work is carried out in thrree cohorts we have available. The first group is the same sample of over 600 children who participate in the genetic study as just described. The second group is a set of identical (monozygotic) twins recruited from the Michigan Twin Registry (in collaboration with Dr. Klump and Dr. Burt). By examining epigenetic variation in identical twins who are discordant for ADHD, we can isolate unique epigenetic effects and obtain convergent information. Third, for additional application we have a bank of hundreds of DNA samples from a case-control cohort in Michigan that can be analyzed if needed.

Productivity. This is a new initiative that has recently begun. To date we have launched the studies described, assembled the collaborative and consultative expert team, set up the infrastrsucture and pipeline for analysis at OHSU (with the assistance of Dr. Harrington and the genomics core facility at OHSU), presented several studies at major conferences and published one paper, and initiated pilot data analyses of epigenetic findings that are in preparation for publication.