New York: Apart from dementia caused by Alzheimer's disease in the elderly, there are many, relatively rare causes like dementia with Lewy Bodies, vascular dementia, and frontotemporal dementia.
Scientists have identified new genetic risk factors for two types of non-Alzheimer's dementia. The team from the US National Institutes of Health (NIH) discovered several structural variants that could be risk factors to Lewy body dementia (LBD) and frontotemporal dementia (FTD). Their findings are published in the journal Cell Genomics.
Structural variants have been implicated in a variety of neurological disorders. Unlike more commonly studied mutations, which often affect one or a few DNA building blocks called nucleotides, structural variants represent at least 50 but often hundreds, or even thousands, of nucleotides at once, making them more challenging to study.
"If you imagine that our entire genetic code is a book, a structural variant would be a paragraph, page, or even an entire chapter that has been removed, duplicated, or inserted in the wrong place," said Sonja W. Scholz, an investigator in the neurogenetics branch of the US National Institute of Neurological Disorders and Stroke (NINDS), part of NIH, in a statement.
By combining cutting-edge computer algorithms capable of mapping structural variations across the whole genome with machine learning, the research team analysed whole-genome data from thousands of patient samples and several thousand unaffected controls.
A previously unknown variant in the gene TCPN1 was found in samples from patients with LBD, a disease that is like Parkinson's and is associated with abnormal deposits of the protein alpha-synuclein in the brain. This variant, in which more than 300 nucleotides are deleted from the gene, is associated with a higher risk of developing LBD.
While the finding is new for LBD, TCPN1 is a known risk factor for Alzheimer's, which could mean that this structural variant plays a role in the broader dementia population.
"From a genetics standpoint, this is a very exciting finding," said Scholz. "It provides a point of reference for cell biology and animal model studies and possibly down the road, a target for intervention."
By looking at a group of 50 genes implicated in inherited neurodegenerative diseases, the investigators were able to identify additional rare structural variants, including several that are known to cause disease.
The analyses also identified two well-established risk factors for FTD changes in the C9orf72 and MAPT genes. These proof-of-concept findings bolstered the strength of the study's new findings by demonstrating that the algorithms were properly working.
Because reference maps for currently-available structural variants are limited, the researchers generated a catalogue based on the data obtained in these analyses.