Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias

Cell Genom. 2023 May 4;3(6):100316. doi: 10.1016/j.xgen.2023.100316. eCollection 2023 Jun 14.


We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Keywords: Lewy body dementia; amyotrophic lateral sclerosis; case-control study; frontotemporal dementia; genome-wide association study; non–Alzheimer's dementia; resource; structural variant.