26 October 2012. With its ever-dropping price tag, whole-genome sequencing is taking off in Alzheimer's research. Several new collaborative projects aim to use this technology to more deeply understand Alzheimer's disease and find genetic clues to better diagnostics and therapeutics. In the latest such venture, the Cure Alzheimer's Fund donated $5.4 million to Massachusetts General Hospital in Boston (see press release) to sequence 1,500 samples from a DNA repository collected from members of families with AD. Scientists from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) have also started sequencing all of its participants' genomes.
"There are several sequencing projects in progress or in the planning stages, so this is an exciting time for AD genetics research," said Alison Goate, Washington University in St. Louis, Missouri. "These sequencing efforts are important because they represent some of the first to apply whole-genome sequencing approaches in AD."
From the beginning of November this year until about mid-summer 2013, scientists led by Rudolph Tanzi of Mass General will partner with Illumina, Inc., to sequence all 1,500 genomes kept in the National Institute of Mental Health (NIMH) AD family sample. Most DNA in the repository comes from sporadic AD patients and their relations, but a small subset was taken from families who have early-onset AD with unknown genetic mutations. In addition to these samples, the team will sequence genomes from a brain repository kept by Bradley Hyman and Teresa Gomez-Isla, also at Mass General. About 100 people who died with normal cognition but turned out to have significant AD pathology donated those tissues.
Comparing whole-genome sequences from those with and without AD or cognitive deficits will allow scientists to find more than just the genetic risk markers that genomewide association studies provide, said Tanzi. "The ultimate goal of any genetics experiment is to find the functional change in the DNA that matters biologically, and that requires whole-genome sequencing," he told Alzforum. "Now, the cost has come down enough that we can afford to sequence the whole genome in these large cohorts." Mass General will manage and analyze the data and provide access to scientists around the globe through NIH public databases.
The Mass General news follows last July’s announcement of a similar push within ADNI to sequence the genomes of all 800-plus participants. Scientists already have longitudinal neuroimaging and fluid biomarkers for these individuals. Researchers have sequenced more than 100 ADNI genomes thus far, and the rest may be completed within the next six months, said Arthur Toga, University of California School of Medicine in Los Angeles. Illumina will help sequence all the genomes, with funding from the Alzheimer's Association and the Brin Wojcicki Foundation, led by Google co-founder Sergey Brin and 23andMe co-founder Anne Wojcicki. After various quality control measures are complete, the data could be publicly available in the next nine months, though the time frame is not certain. Perhaps the greatest challenge is figuring out how to disseminate such large amounts of data, expected to reach nearly 200 terabytes, Toga said.
These large-scale projects add to at least one other large whole-genome sequencing effort afoot. The New York Genome Center and The Feinstein Institute for Medical Research announced in February that they, too, would partner with Illumina to sequence up to 1,000 AD patient genomes over four years. The goal is to compare these genomes to those from a group of healthy elderly controls to investigate genetic risk for AD and find the underlying molecular pathways of neuronal degeneration. Once compiled, data will be freely available to the scientific community.
"The most important aspect of each of these projects is that the data will be shared," said Goate. "It is very likely that we will need to combine sequencing data across multiple studies to have good power to identify rare variants of large effect."
Not only that, but having publicly available data means that many more scientists will be engaged in studies than otherwise, said Toga. "There are a lot of people who may have potentially creative and innovative ways of analyzing the data that maybe we didn't think of," he told Alzforum. "The more people we engage, the better the likelihood that these tough problems will be solved."—Gwyneth Dickey Zakaib.