Older woman losing parts of head and looking confused as a symbol of dementia.
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Researchers have discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for Lewy Body Dementia (LBD). Since TCPN1 is a known risk factor for Alzheimer’s disease, this could mean that it plays a role in the broader dementia population.

The team also detected the known structural variants at the C9orf72 and MAPT loci as associated with frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS), which reinforced that the team’s algorithms were properly working. Note: The discovery of repeat expansions in C9orf72 led clinicians to pair frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in the same clinical spectrum.

The team also assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia. These are non-Alzheimer’s dementias, with LBD being the second most common form of this type of neurodegeneration after Alzheimer’s.

The work was led by Sonja W. Scholz, of Johns Hopkins University and appeared this month in Cell Genomics. The lead author is Karri Kaivota of the National Institute of Neurological Disorders and Stroke. The project was a collaborative effort between scientists at the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) at NIH.

“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.”

For this study, the team applied a structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls.

Structural variants are duplicated, deleted, inserted, inverted, or translocated DNA segments measuring at least 50 base pairs in length. Unlike more commonly studied mutations, which often affect one or a few nucleotides, structural variants represent at least 50 but often hundreds, or even thousands, of nucleotides at once, making them more challenging to study.

They are also considered a major source of genetic diversity and have been implicated in the pathogenesis of complex neurological disorders.

The study authors write: “To date, identifying the structural variants underlying disease has relied on candidate-gene studies rather than unbiased genome-wide assessments. More recently, however, the study of structural variants has gained momentum due to the improved availability of whole-genome sequence datasets and modernized detection algorithms.”

The team set out to systematically map, via genome-wide association studies, structural variants in large cohorts of patients diagnosed with non-Alzheimer’s dementias (LBD and FTD/ALS) and in unaffected controls.

Besides discovering a common structural variant in TPCN1 that modulates disease risk in LBD they also detected found a break-end mutation at chromosome 9p21.2, corresponding to the C9orf72 hexanucleotide repeat expansion, and a 673-kb complex inversion related to the MAPT H2 haplotype. Both are structural variants known to be associated with FTD/ALS.

Because reference maps for currently-available structural variants are limited, the researchers generated a catalog based on the data obtained in these analyses. The analysis code and all the raw data are now available to the scientific community for use in their studies.

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