Alzheimer’s genetics research has truly entered the genomic era. On December 2, the National Institutes of Health released the first batch of whole-genome sequence data from the Alzheimer’s Disease Sequencing Project (ADSP). The ADSP represents one of the first projects mandated by the National Plan to Address Alzheimer’s Disease (see Jan 2012 news story). The sequences completed to date comprise the genomes of 410 people from 89 families affected by AD. The release follows the September unveiling of full genetic sequences from 809 people enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (see Oct 2013 news story). Similar initiatives are underway as well, such as the Alzheimer’s Genome Project and the International Genomics of Alzheimer’s Project (IGAP) (see Aug 2013 news story).
Why the surge in AD genomic studies? In recent years, Alzheimer’s genetic research has relied mostly on large genome-wide association studies (GWAS) to find risk genes. However, GWAS see only about 1 million bases out of the 3.3 billion in the human genome, and often cannot pin down the variants that directly affect disease risk. “Now, with the growing numbers of available whole-genome and whole-exome sequences, we can fill the gap and determine the DNA variants in these genes that pathogenically explain risk. This will allow for meaningful translational studies, new animal models, and screening for therapeutics addressing known and novel pathways,” Rudy Tanzi at Massachusetts General Hospital, Charlestown, wrote to Alzforum.
Analyzing the full sequence will also help identify regions of the genome that regulate gene function, said Marilyn Miller, who heads the Alzheimer’s disease genetics program at the National Institute on Aging (NIA). The NIA and the National Human Genome Research Institute (NHGRI) jointly run the ADSP. “With this information, we can begin to understand how genes work together to produce the symptoms of Alzheimer’s disease. We may find that there are different phenotypes of AD that have different gene combinations associated with them,” she told Alzforum. Adam Felsenfeld, who directs NHGRI’s Genome Sequencing Program, said that the ADSP study was designed to detect both risk and protective alleles. “Protective alleles can provide exciting insights into potential routes for therapeutics,” he noted.
Researchers can request access to ADSP data at the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), or at the Database of Genotypes and Phenotypes (dbGaP) maintained by the National Center for Biotechnology Information (NCBI).
The ADSP genomic data come from several cohorts, including the NIA-Late Onset of Alzheimer’s Disease (NIA LOAD); the National Cell Repository for Alzheimer’s Disease (NCRAD); the Alzheimer’s Disease Genetics Consortium (ADGC); and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). The dataset includes demographic and phenotypic information, such as Alzheimer’s symptoms. Some subsets of samples also contain biomarker and neuropathology data. In addition, the cohort includes a large number of people of Caribbean Hispanic descent. “This will help us explore whether genes operate differently in different ethnic subgroups,” Miller said.
Miller expects whole-genome data from the full cohort of 582 people from 111 families to be released in early 2014. The project will also complete exome sequencing on an additional 6,000 people with AD and 5,000 controls. That data will likely come out in summer 2014, Miller said. Afterward, project researchers will attempt to replicate any findings of risk and protective alleles in a separate cohort of several thousand people.
How will all these genomic projects fit together? Miller said that ADNI researchers have agreed to import their data into the NIAGADS database. At some point, the two datasets may be combined. Researchers will add other sequencing projects to NIAGADS as they become available, she said. Likewise, data from the Alzheimer’s Genome Project will be added to public databases, Tanzi told Alzforum. For Alzheimer’s researchers, the result may be a genomics treasure trove to sift through.—Madolyn Bowman Rogers
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