. 2023 May 4;3(6):100316.

doi: 10.1016/j.xgen.2023.100316. eCollection 2023 Jun 14.

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

Karri Kaivola¹, Ruth Chia², Jinhui Ding³, Memoona Rasheed², Masashi Fujita⁴, Vilas Menon⁴, Ronald L Walton⁵, Ryan L Collins^{6

7

8}, Kimberley Billingsley^{9

10}, Harrison Brand^{6

7

8}, Michael Talkowski^{6

7

11}, Xuefang Zhao^{6

7}, Ramita Dewan², Ali Stark², Anindita Ray¹, Sultana Solaiman¹, Pilar Alvarez Jerez^{9

10}, Laksh Malik¹⁰, Ted M Dawson^{12

13

14

15}, Liana S Rosenthal¹², Marilyn S Albert¹², Olga Pletnikova^{16

17}, Juan C Troncoso¹⁷, Mario Masellis^{18

19

20

21}, Julia Keith²², Sandra E Black^{19

23

24

20

21}, Luigi Ferrucci²⁵, Susan M Resnick²⁶, Toshiko Tanaka²⁵; American Genome Center; International LBD Genomics Consortium; International ALS/FTD Consortium; PROSPECT Consortium; Eric Topol²⁷, Ali Torkamani²⁷, Pentti Tienari^{28

29}, Tatiana M Foroud³⁰, Bernardino Ghetti³¹, John E Landers³², Mina Ryten^{33

34

35}, Huw R Morris^{36

37}, John A Hardy^{36

37

38

39}, Letizia Mazzini⁴⁰, Sandra D'Alfonso⁴¹, Cristina Moglia^{42

43}, Andrea Calvo^{42

43}, Geidy E Serrano⁴⁴, Thomas G Beach⁴⁴, Tanis Ferman⁴⁵, Neill R Graff-Radford⁴⁶, Bradley F Boeve⁴⁷, Zbigniew K Wszolek⁴⁸, Dennis W Dickson⁵, Adriano Chiò^{42

43

48}, David A Bennett⁴⁹, Philip L De Jager⁴, Owen A Ross⁵, Clifton L Dalgard^{50

51}, J Raphael Gibbs³, Bryan J Traynor^{2

12

52}, Sonja W Scholz^{1

12}

Collaborators, Affiliations

Collaborators

Anthony R Soltis, Coralie Viollet, Gauthaman Sukumar, Camille Alba, Nathaniel Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bacikova, Xijun Zhang, Daniel N Hupalo, Adelani Adeleye, Matthew D Wilkerson, Harvey B Pollard, Clifton L Dalgard, Sandra E Black, Ziv Gan-Or, Julia Keith, Mario Masellis, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Andrea Calvo, Antonio Canosa, Adriano Chio, Giancarlo Logroscino, Gabriele Mora, Reijko Krüger, Patrick May, Daniel Alcolea, Jordi Clarimon, Juan Fortea, Isabel Gonzalez-Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pastor, Pascual Sanchez-Juan, Francesca Brett, Dag Aarsland, Safa Al-Sarraj, Johannes Attems, Steve Gentleman, John A Hardy, Angela K Hodges, Seth Love, Ian G McKeith, Christopher M Morris, Huw R Morris, Laura Palmer, Stuart Pickering-Brown, Mina Ryten, Alan J Thomas, Claire Troakes, Marilyn S Albert, Matthew J Barrett, Thomas G Beach, Lynn M Bekris, David A Bennett, Bradley F Boeve, Clifton L Dalgard, Ted M Dawson, Dennis W Dickson, Kelley Faber, Tanis Ferman, Luigi Ferrucci, Margaret E Flanagan, Tatiana M Foroud, Bernardino Ghetti, J Raphael Gibbs, Alison Goate, David S Goldstein, Neill R Graff-Radford, Horacio Kaufmann, Walter A Kukull, James B Leverenz, Grisel Lopez, Qinwen Mao, Eliezer Masliah, Edwin Monuki, Kathy L Newell, Jose-Alberto Palma, Matthew Perkins, Olga Pletnikova, Alan E Renton, Susan M Resnick, Liana S Rosenthal, Owen A Ross, Clemens R Scherzer, Geidy E Serrano, Vikram G Shakkottai, Ellen Sidransky, Toshiko Tanaka, Nahid Tayebi, Eric Topol, Ali Torkamani, Juan C Troncoso, Randy Woltjer, Zbigniew K Wszolek, Sonja W Scholz, Robert H Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, Adriano Chiò, John Cooper-Knock, Carsten Drepper, Vivian E Drory, Travis L Dunckley, Eva Feldman, Pietro Fratta, Glenn Gerhard, Summer B Gibson, Jonathan D Glass, John A Hardy, Matthew B Harms, Terry D Heiman-Patterson, Lilja Jansson, Janine Kirby, Justin Kwan, Hannu Laaksovirta, John E Landers, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel Jl MacGowan, Nicholas J Maragakis, Kevin Mouzat, Liisa Myllykangas, Richard W Orrell, Lyle W Ostrow, Roger Pamphlett, Erik Pioro, Stefan M Pulst, John M Ravits, Wim Robberecht, Ekaterina Rogaeva, Jeffrey D Rothstein, Michael Sendtner, Pamela J Shaw, Katie C Sidle, Zachary Simmons, Thor Stein, David J Stone, Pentti J Tienari, Bryan J Traynor, Juan C Troncoso, Miko Valori, Philip Van Damme, Vivianna M Van Deerlin, Ludo Van Den Bosch, Lorne Zinman

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
³ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴ Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
⁵ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA.
⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (M.I.T.), Cambridge, MA, USA.
⁸ Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
¹⁰ Centre for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
¹¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹² Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹³ Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁴ Department of Pharmacology and Molecular Science, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁵ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁶ Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY, USA.
¹⁷ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁸ Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
¹⁹ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
²⁰ Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada.
²¹ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada.
²² Department of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
²³ Institute of Medical Science, Faculty of Medicine, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
²⁴ Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
²⁵ Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA.
²⁶ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
²⁷ Scripps Research Translational Institute, Scripps Research, La Jolla, CA, USA.
²⁸ Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
²⁹ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³¹ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
³² Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
³³ Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, University College London, London, UK.
³⁴ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
³⁵ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
³⁶ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
³⁷ UCL Movement Disorders Centre, University College London, London, UK.
³⁸ UK Dementia Research Institute, Department of Neurogenerative Disease and Reta Lila Weston Institute, London, UK.
³⁹ Institute of Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁴⁰ Maggiore della Carita University Hospital, Novara, Italy.
⁴¹ Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
⁴² Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
⁴³ Azienda Ospedaliero Universitaria Città, della Salute e della Scienza, Corso Bramante, 88, Turin, Italy.
⁴⁴ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁴⁵ Department of Psychiatry and Psychology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA.
⁴⁶ Department of Neurology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA.
⁴⁷ Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA.
⁴⁸ Institute of Cognitive Sciences and Technologies, C.N.R., Via S. Martino della Battaglia, 44, Rome, Italy.
⁴⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵⁰ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵¹ The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵² RNA Therapeutics Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, Rockville, MD, USA.

PMID: 37388914
PMCID: PMC10300553
DOI: 10.1016/j.xgen.2023.100316

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

Karri Kaivola et al. Cell Genom. 2023.

. 2023 May 4;3(6):100316.

doi: 10.1016/j.xgen.2023.100316. eCollection 2023 Jun 14.

Authors

Collaborators

Anthony R Soltis, Coralie Viollet, Gauthaman Sukumar, Camille Alba, Nathaniel Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bacikova, Xijun Zhang, Daniel N Hupalo, Adelani Adeleye, Matthew D Wilkerson, Harvey B Pollard, Clifton L Dalgard, Sandra E Black, Ziv Gan-Or, Julia Keith, Mario Masellis, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Andrea Calvo, Antonio Canosa, Adriano Chio, Giancarlo Logroscino, Gabriele Mora, Reijko Krüger, Patrick May, Daniel Alcolea, Jordi Clarimon, Juan Fortea, Isabel Gonzalez-Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pastor, Pascual Sanchez-Juan, Francesca Brett, Dag Aarsland, Safa Al-Sarraj, Johannes Attems, Steve Gentleman, John A Hardy, Angela K Hodges, Seth Love, Ian G McKeith, Christopher M Morris, Huw R Morris, Laura Palmer, Stuart Pickering-Brown, Mina Ryten, Alan J Thomas, Claire Troakes, Marilyn S Albert, Matthew J Barrett, Thomas G Beach, Lynn M Bekris, David A Bennett, Bradley F Boeve, Clifton L Dalgard, Ted M Dawson, Dennis W Dickson, Kelley Faber, Tanis Ferman, Luigi Ferrucci, Margaret E Flanagan, Tatiana M Foroud, Bernardino Ghetti, J Raphael Gibbs, Alison Goate, David S Goldstein, Neill R Graff-Radford, Horacio Kaufmann, Walter A Kukull, James B Leverenz, Grisel Lopez, Qinwen Mao, Eliezer Masliah, Edwin Monuki, Kathy L Newell, Jose-Alberto Palma, Matthew Perkins, Olga Pletnikova, Alan E Renton, Susan M Resnick, Liana S Rosenthal, Owen A Ross, Clemens R Scherzer, Geidy E Serrano, Vikram G Shakkottai, Ellen Sidransky, Toshiko Tanaka, Nahid Tayebi, Eric Topol, Ali Torkamani, Juan C Troncoso, Randy Woltjer, Zbigniew K Wszolek, Sonja W Scholz, Robert H Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, Adriano Chiò, John Cooper-Knock, Carsten Drepper, Vivian E Drory, Travis L Dunckley, Eva Feldman, Pietro Fratta, Glenn Gerhard, Summer B Gibson, Jonathan D Glass, John A Hardy, Matthew B Harms, Terry D Heiman-Patterson, Lilja Jansson, Janine Kirby, Justin Kwan, Hannu Laaksovirta, John E Landers, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel Jl MacGowan, Nicholas J Maragakis, Kevin Mouzat, Liisa Myllykangas, Richard W Orrell, Lyle W Ostrow, Roger Pamphlett, Erik Pioro, Stefan M Pulst, John M Ravits, Wim Robberecht, Ekaterina Rogaeva, Jeffrey D Rothstein, Michael Sendtner, Pamela J Shaw, Katie C Sidle, Zachary Simmons, Thor Stein, David J Stone, Pentti J Tienari, Bryan J Traynor, Juan C Troncoso, Miko Valori, Philip Van Damme, Vivianna M Van Deerlin, Ludo Van Den Bosch, Lorne Zinman

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
³ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴ Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
⁵ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA.
⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (M.I.T.), Cambridge, MA, USA.
⁸ Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
¹⁰ Centre for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
¹¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹² Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹³ Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁴ Department of Pharmacology and Molecular Science, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁵ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁶ Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY, USA.
¹⁷ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁸ Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
¹⁹ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
²⁰ Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada.
²¹ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada.
²² Department of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
²³ Institute of Medical Science, Faculty of Medicine, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
²⁴ Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON, Canada.
²⁵ Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA.
²⁶ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
²⁷ Scripps Research Translational Institute, Scripps Research, La Jolla, CA, USA.
²⁸ Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
²⁹ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³¹ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
³² Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
³³ Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, University College London, London, UK.
³⁴ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
³⁵ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
³⁶ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
³⁷ UCL Movement Disorders Centre, University College London, London, UK.
³⁸ UK Dementia Research Institute, Department of Neurogenerative Disease and Reta Lila Weston Institute, London, UK.
³⁹ Institute of Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁴⁰ Maggiore della Carita University Hospital, Novara, Italy.
⁴¹ Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
⁴² Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
⁴³ Azienda Ospedaliero Universitaria Città, della Salute e della Scienza, Corso Bramante, 88, Turin, Italy.
⁴⁴ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁴⁵ Department of Psychiatry and Psychology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA.
⁴⁶ Department of Neurology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA.
⁴⁷ Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA.
⁴⁸ Institute of Cognitive Sciences and Technologies, C.N.R., Via S. Martino della Battaglia, 44, Rome, Italy.
⁴⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵⁰ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵¹ The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵² RNA Therapeutics Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, Rockville, MD, USA.

PMID: 37388914
PMCID: PMC10300553
DOI: 10.1016/j.xgen.2023.100316

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.

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

PubMed Disclaimer

Conflict of interest statement

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).

Figures

**Figure 1**
Study flowchart Schematic illustration of the analytical workflow. The same controls were used in the analysis of LBD and FTD/ALS.

**Figure 2**
Descriptive statistics of the structural variants in the study cohorts Descriptive statistics of high-quality subset of structural variants mapped by the GATK-SV pipeline in the (A) LBD case-control cohort and (B) FTD/ALS case-control cohort. AF, allele frequency; DEL, deletions; DUP, duplications; INS, insertions; INV, inversions; CPX, complex variant; OTH, other variant; SV, structural variant.

**Figure 3**
Genome-wide representation of the common structural variants in the FTD/ALS case-control cohort Manhattan plot depicting the GWAS results (n = 2,307 FTD and 3,677 controls, and 4,699 structural variants with MAF ≥ 1%). The annotations show the break-end variant on chromosome 9, corresponding to the *C9orf72* hexanucleotide repeat expansion, and a 673-kb complex inversion that is part of the *MAPT* H2 haplotype.

**Figure 4**
Genome-wide representation of the common structural variants in LBD For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.xgen.2023.100316. (A) Manhattan plot depicting the GWAS results (n = 2,355 LBD cases and 3,700 controls; 4,889 structural variants with MAF > 1%). (B) An illustration of the *TPCN1* deletion in a heterozygous carrier. Paired-end reads that did not span the deletion have been omitted for clarity. (C) The *TPCN1* deletion (purple diamond) is the top association signal in the LBD analysis and shows strong linkage disequilibrium with nearby single-nucleotide variants.

**Figure 5**
Genomic fine-mapping of the *TPCN1* locus (A) Scatterplot showing the beta regression coefficients of common variants (MAF ≥ 1%) at the *TPCN1* locus in the Chia et al. LBD GWAS (y axis) and Bellenguez et al. Alzheimer’s disease GWAS (x axis). (B) Beta-beta plot comparing the *TPCN1* locus variants in the Chia et al. LBD GWAS (y axis) with the Nalls et al. Parkinson’s disease GWAS results (excluding 23&Me data; x axis). (C) Single-nucleus RNA sequence analysis of the *TPCN1* deletion-tagging SNP rs6489896 identified a significant *cis*-eQTL for *RITA1* in excitatory neurons.

**Figure 6**
Interactive catalog of structural variants in non-Alzheimer’s dementias (A) Screen shot of the online portal that lets the user filter structural variants and display genomic regions. For example, this image shows a large duplication encompassing the entire *SNCA* gene in an LBD case. (B) Visualization of structural variants using BigBed files in the Ensembl genome browsers as custom tracks (https://www.ensembl.org).

See this image and copyright information in PMC

References

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous