Whole-Genome Sequencing Suggests New Approaches to Drug Development for Alzheimer's Disease
Key findings
- In this study, whole-genome sequencing was used to search for associations of rare gene variants with Alzheimer's disease (AD) in 2,247 subjects from 605 families in which more than one member had an AD diagnosis
- 13 rare-variant signals (four from single-variant analyses, nine from spatial-clustering analyses) exhibited associations with AD in the families as well as in a replication cohort of 1,669 unrelated individuals
- The most highly significant rare single nucleotide variant was LINC00298, which is non-coding and of unknown function
- Pathway analyses suggested the genes associated with the rare variants have roles in development of neurons, neuroplasticity and loss of synapses, the neurologic change most closely correlated with severity of AD
- The results emphasize the importance of studying rare variants from whole genome sequencing for a better understanding of the genetic and functional basis of AD
Genetics is well documented to play a crucial role in susceptibility to late-onset Alzheimer's disease (AD). Previous information about genetic risk factors has come from more than 75 genome-wide association studies (GWAS), including pioneering research at Massachusetts General Hospital, in which the genomes of thousands of individuals are scanned to search for association of AD with common gene variants.
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Now, taking a different tack, Mass General researchers have completed the first systematic study to search for rare variants associated with AD using whole-genome sequencing data. Unlike GWAS, this method scans every bit of DNA in a genome, so it can identify rare variants associated with a disease. The new study detected 13 rare variants and, for the first time, linked AD genes directly to neuroplasticity and loss of synapses, the neurologic change most closely correlated with severity of AD.
Dmitry Prokopenko, PhD, an instructor in the Department of Neurology at Mass General, and Rudolph E. Tanzi, PhD, co-director of the McCance Center for Brain Health and vice-chair of the Department of Neurology, and colleagues published their findings in Alzheimer's & Dementia.
Study Cohorts
The sequencing focused on rare variants with minor allele frequency <1%. It was performed on genomes of 2,247 individuals from 605 families ("discovery cohort") participating in the Alzheimer's Disease Sequencing Project sponsored by the U.S. government. In these families, more than one member was diagnosed with AD.
Suggestive findings were validated using data from a previous whole-genome sequencing study that involved 1,669 unrelated individuals ("replication cohort").
Novel Potential AD Loci
The results revealed 13 gene variants previously unknown to be associated with AD, with consistent signals in both the discovery and replication cohorts. Four variants were detected in single-variant testing and nine in spatial clustering–derived (region-based) testing.
The most highly significant single nucleotide variant was LINC00298, a long stretch of non-coding RNA that occurs between genes and does not code for a protein. Its functional role is not known, but it is thought to help regulate neuroplasticity.
Functional Profile
Pathway analyses suggested the genes associated with the rare variants have roles in neuroplasticity, synaptic function and integrity, axonal maintenance, development of heart tissue and development of neurons.
In contrast, genes that have been identified through common-variant associations in genome-wide association studies are more involved in the immune-system response, lipid metabolism and deposition of amyloid-beta.
Future Directions
The stark difference in functional profiles implies rare variants make essential contributions to the development of AD, which seem to be based largely on neuronal and synaptic function.
Therefore, the findings suggest new approaches and targets for developing therapeutic or even preventive drugs for AD. This study also affirms the power of whole-genome sequencing for research into AD and other neurologic diseases.
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