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

Karri Kaivola; Ruth Chia; Jinhui Ding; Memoona Rasheed; Masashi Fujita; Vilas Menon; Ronald L. Walton; Ryan L. Collins; Kimberley Billingsley; Harrison Brand; Michael Talkowski; Xuefang Zhao; Ramita Dewan; Ali Stark; Anindita Ray; Sultana Solaiman; Pilar Alvarez Jerez; Laksh Malik; Ted M. Dawson; Liana S. Rosenthal; Marilyn S. Albert; Olga Pletnikova; Juan C. Troncoso; Mario Masellis; Julia Keith; Sandra E. Black; Luigi Ferrucci; Susan M. Resnick; Toshiko Tanaka; 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; Ziv Gan-Or; Ekaterina Rogaeva; Alexis Brice; Suzanne Lesage; Georgia Xiromerisiou; Reijko Krüger; PROSPECT Consortium; The American Genome Center; International LBD Genomics Consortium; International ALS/FTD Consortium; Sonja W. Scholz

doi:10.1016/j.xgen.2023.100316

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

Karri Kaivola, Ruth Chia, Jinhui Ding, Memoona Rasheed, Masashi Fujita, Vilas Menon, Ronald L. Walton, Ryan L. Collins, Kimberley Billingsley, Harrison Brand, Michael Talkowski, Xuefang Zhao, Ramita Dewan, Ali Stark, Anindita Ray, Sultana Solaiman, Pilar Alvarez Jerez, Laksh Malik, Ted M. Dawson, Liana S. RosenthalMarilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Mario Masellis, Julia Keith, Sandra E. Black, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, 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, Ziv Gan-Or, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Reijko Krüger, PROSPECT Consortium, The American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, Sonja W. Scholz^*

^*Corresponding author for this work

Transversal Translational Medicine

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

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
Article number	100316
Journal	Cell Genomics
Volume	3
Issue number	6
DOIs	https://doi.org/10.1016/j.xgen.2023.100316
Publication status	Published - 14 Jun 2023

Keywords

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

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Kaivola, K., Chia, R., Ding, J., Rasheed, M., Fujita, M., Menon, V., Walton, R. L., Collins, R. L., Billingsley, K., Brand, H., Talkowski, M., Zhao, X., Dewan, R., Stark, A., Ray, A., Solaiman, S., Alvarez Jerez, P., Malik, L., Dawson, T. M., ... Scholz, S. W. (2023). Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias. Cell Genomics, 3(6), Article 100316. https://doi.org/10.1016/j.xgen.2023.100316

@article{ddbe8ff385444cd6bde2c6378170c668,

title = "Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias",

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",

author = "Karri Kaivola and Ruth Chia and Jinhui Ding and Memoona Rasheed and Masashi Fujita and Vilas Menon and Walton, {Ronald L.} and Collins, {Ryan L.} and Kimberley Billingsley and Harrison Brand and Michael Talkowski and Xuefang Zhao and Ramita Dewan and Ali Stark and Anindita Ray and Sultana Solaiman and {Alvarez Jerez}, Pilar and Laksh Malik and Dawson, {Ted M.} and Rosenthal, {Liana S.} and Albert, {Marilyn S.} and Olga Pletnikova and Troncoso, {Juan C.} and Mario Masellis and Julia Keith and Black, {Sandra E.} and Luigi Ferrucci and Resnick, {Susan M.} and Toshiko Tanaka and Soltis, {Anthony R.} and Coralie Viollet and Gauthaman Sukumar and Camille Alba and Nathaniel Lott and {McGrath Martinez}, Elisa and Meila Tuck and Jatinder Singh and Dagmar Bacikova and Xijun Zhang and Hupalo, {Daniel N.} and Adelani Adeleye and Wilkerson, {Matthew D.} and Pollard, {Harvey B.} and Dalgard, {Clifton L.} and Ziv Gan-Or and Ekaterina Rogaeva and Alexis Brice and Suzanne Lesage and Georgia Xiromerisiou and Reijko Kr{\"u}ger and {PROSPECT Consortium} and {The American Genome Center} and {International LBD Genomics Consortium} and {International ALS/FTD Consortium} and Scholz, {Sonja W.}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jun,

day = "14",

doi = "10.1016/j.xgen.2023.100316",

language = "English",

volume = "3",

journal = "Cell Genomics",

issn = "2666-979X",

publisher = "Cell Press",

number = "6",

}

Kaivola, K, Chia, R, Ding, J, Rasheed, M, Fujita, M, Menon, V, Walton, RL, Collins, RL, Billingsley, K, Brand, H, Talkowski, M, Zhao, X, Dewan, R, Stark, A, Ray, A, Solaiman, S, Alvarez Jerez, P, Malik, L, Dawson, TM, Rosenthal, LS, Albert, MS, Pletnikova, O, Troncoso, JC, Masellis, M, Keith, J, Black, SE, Ferrucci, L, Resnick, SM, Tanaka, T, Soltis, AR, Viollet, C, Sukumar, G, Alba, C, Lott, N, McGrath Martinez, E, Tuck, M, Singh, J, Bacikova, D, Zhang, X, Hupalo, DN, Adeleye, A, Wilkerson, MD, Pollard, HB, Dalgard, CL, Gan-Or, Z, Rogaeva, E, Brice, A, Lesage, S, Xiromerisiou, G, Krüger, R, PROSPECT Consortium, The American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium & Scholz, SW 2023, 'Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias', Cell Genomics, vol. 3, no. 6, 100316. https://doi.org/10.1016/j.xgen.2023.100316

TY - JOUR

T1 - Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias

AU - Kaivola, Karri

AU - Chia, Ruth

AU - Ding, Jinhui

AU - Rasheed, Memoona

AU - Fujita, Masashi

AU - Menon, Vilas

AU - Walton, Ronald L.

AU - Collins, Ryan L.

AU - Billingsley, Kimberley

AU - Brand, Harrison

AU - Talkowski, Michael

AU - Zhao, Xuefang

AU - Dewan, Ramita

AU - Stark, Ali

AU - Ray, Anindita

AU - Solaiman, Sultana

AU - Alvarez Jerez, Pilar

AU - Malik, Laksh

AU - Dawson, Ted M.

AU - Rosenthal, Liana S.

AU - Albert, Marilyn S.

AU - Pletnikova, Olga

AU - Troncoso, Juan C.

AU - Masellis, Mario

AU - Keith, Julia

AU - Black, Sandra E.

AU - Ferrucci, Luigi

AU - Resnick, Susan M.

AU - Tanaka, Toshiko

AU - Soltis, Anthony R.

AU - Viollet, Coralie

AU - Sukumar, Gauthaman

AU - Alba, Camille

AU - Lott, Nathaniel

AU - McGrath Martinez, Elisa

AU - Tuck, Meila

AU - Singh, Jatinder

AU - Bacikova, Dagmar

AU - Zhang, Xijun

AU - Hupalo, Daniel N.

AU - Adeleye, Adelani

AU - Wilkerson, Matthew D.

AU - Pollard, Harvey B.

AU - Dalgard, Clifton L.

AU - Gan-Or, Ziv

AU - Rogaeva, Ekaterina

AU - Brice, Alexis

AU - Lesage, Suzanne

AU - Xiromerisiou, Georgia

AU - Krüger, Reijko

AU - PROSPECT Consortium

AU - The American Genome Center

AU - International LBD Genomics Consortium

AU - International ALS/FTD Consortium

AU - Scholz, Sonja W.

PY - 2023/6/14

Y1 - 2023/6/14

N2 - 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.

AB - 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.

KW - Lewy body dementia

KW - amyotrophic lateral sclerosis

KW - case-control study

KW - frontotemporal dementia

KW - genome-wide association study

KW - non–Alzheimer's dementia

KW - resource

KW - structural variant

UR - http://www.scopus.com/inward/record.url?scp=85161957826&partnerID=8YFLogxK

UR - https://pubmed.ncbi.nlm.nih.gov/37388914/

U2 - 10.1016/j.xgen.2023.100316

DO - 10.1016/j.xgen.2023.100316

M3 - Article

AN - SCOPUS:85161957826

SN - 2666-979X

VL - 3

JO - Cell Genomics

JF - Cell Genomics

IS - 6

M1 - 100316

ER -

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

Abstract

Keywords

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