Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 100316 |
| Journal | Cell Genomics |
| Volume | 3 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 14 2023 |
Funding
The authors are grateful to all patients, their family members, and caregivers, as well as all healthy participants, for making this study possible. This research was supported in part by the Intramural Research Program of the US National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers 1ZIAAG000935 [PI B.J.T.], 1ZIANS003154 [PI S.W.S.]). K.K. was supported by grants from The Päivikki and Sakari Sohlberg Foundation and the Finnish Parkinson Foundation . We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, for the provision of human biological materials. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke ( U24 NS072026 , National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging ( P30 AG19610 and P30 AG072980 , Arizona Alzheimer’s Disease Center), the Arizona Department of Health Services (contract 211002 , Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001 , 0011 , 05-901 , and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. The study used tissue samples and data from the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson’s Disease Research (NIH P50 NS38377 ). We thank the members of the Laboratory of Neurogenetics (NIH) for their collegial support and technical assistance. We thank members of the North American Brain Expression Consortium (NABEC) for providing samples derived from brain tissue. Brain tissue for the NABEC cohort was obtained from the Baltimore Longitudinal Study on Aging at the Johns Hopkins School of Medicine, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the Banner Sun Health Research Institute Brain and Body Donation Program, and the University of Kentucky Alzheimer’s Disease Center Brain Bank. We thank the UK Brain Expression Consortium (UKBEC) and the Northwestern University Brain Bank for providing DNA or tissue samples. The ROS/MAP study was supported by the National Institute on Aging ( RF1 AG057473 , U01 AG061356 ). This work utilized the computational resources of the NIH HPC Biowulf cluster USA ( http://hpc.nih.gov ). A complete list of acknowledgments is given in the supplemental information. S.W.S. serves on the Scientific Advisory Council of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. and B.J.T. receive research support from Cerevel Therapeutics. B.J.T. holds patents on the clinical testing and therapeutic implications of the C9orf72 repeat expansion. H.R.M. is employed by the University College London. In the last 12 months, he reports paid consultancy from Roche and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin, and Movement Disorders Society; and research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, and the Michael J Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9orf72 “method for diagnosing a neurodegenerative disease” (PCT/GB2012/052140). The authors are grateful to all patients, their family members, and caregivers, as well as all healthy participants, for making this study possible. This research was supported in part by the Intramural Research Program of the US National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers 1ZIAAG000935 [PI B.J.T.], 1ZIANS003154 [PI S.W.S.]). K.K. was supported by grants from The Päivikki and Sakari Sohlberg Foundation and the Finnish Parkinson Foundation. We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, for the provision of human biological materials. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 and P30 AG072980, Arizona Alzheimer's Disease Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The study used tissue samples and data from the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377). We thank the members of the Laboratory of Neurogenetics (NIH) for their collegial support and technical assistance. We thank members of the North American Brain Expression Consortium (NABEC) for providing samples derived from brain tissue. Brain tissue for the NABEC cohort was obtained from the Baltimore Longitudinal Study on Aging at the Johns Hopkins School of Medicine, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the Banner Sun Health Research Institute Brain and Body Donation Program, and the University of Kentucky Alzheimer's Disease Center Brain Bank. We thank the UK Brain Expression Consortium (UKBEC) and the Northwestern University Brain Bank for providing DNA or tissue samples. The ROS/MAP study was supported by the National Institute on Aging (RF1 AG057473, U01 AG061356). This work utilized the computational resources of the NIH HPC Biowulf cluster USA (http://hpc.nih.gov). A complete list of acknowledgments is given in the supplemental information. Conceptualization, S.W.S. B.J.T. K.B. and J.R.G.; methodology, S.W.S. B.J.T. C.L.D. R.C. K.B. M.R. A.R. and S.S.; software, J.D. J.R.G. R.L.C. H.T. M.B. X.Z. and K.K.; formal analysis, K.K. R.C. J.D. R.L.C. J.R.G. V.M. M.F. D.A.B. and P.L.D.; investigation, K.K. M.R. R.C. C.L.D. R.L.W. R.L.C. A.R. S.S. K.B. P.A.J. L.M. T.M.D. L.S.R. M.S.A. O.P. J.C.T. M.M. J.K. S.E.B. L.F. S.M.R. The American Genome Center; resources, International LBD Genomics Consortium, International ALS/FTD Consortium, E.T. A.T. T.M.F. J.E.L. L.M. S.D. C.M. L.M. S.D. A.C. G.E.S. T.G.B. P.T. T.F. B.G. N.R.G.-R. B.F.B. Z.K.W. D.W.D. A.C. D.A.B. P.L.D. O.A.R. C.L.D. J.R.G. B.J.T. and S.W.S.; data curation, K.K. R.C. J.D. and M.R.; writing – original draft, K.K.; writing – review & editing, all authors; visualization, K.K. J.D. and R.C.; supervision, O.A.R. C.L.D. J.R.G. S.W.S. and B.J.T.; funding acquisition, S.W.S. and B.J.T. S.W.S. serves on the Scientific Advisory Council of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. and B.J.T. receive research support from Cerevel Therapeutics. B.J.T. holds patents on the clinical testing and therapeutic implications of the C9orf72 repeat expansion. H.R.M. is employed by the University College London. In the last 12 months, he reports paid consultancy from Roche and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin, and Movement Disorders Society; and research grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, and the Michael J Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9orf72 “method for diagnosing a neurodegenerative disease” (PCT/GB2012/052140).
Keywords
- Lewy body dementia
- amyotrophic lateral sclerosis
- case-control study
- frontotemporal dementia
- genome-wide association study
- non–Alzheimer's dementia
- resource
- structural variant
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Genetics