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

PROSPECT Consortium; The American Genome Center; International LBD Genomics Consortium; International ALS/FTD Consortium; Karri Kaivola; Ruth Chia; Jinhui Ding; Lilja Jansson; Hannu Laaksovirta; Liisa Myllykangas

doi:10.1016/j.xgen.2023.100316

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

PROSPECT Consortium, The American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, Karri Kaivola, Ruth Chia, Jinhui Ding, Lilja Jansson, Hannu Laaksovirta, Liisa Myllykangas

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

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
Number of pages	21
ISSN	2666-979X
DOIs	https://doi.org/10.1016/j.xgen.2023.100316
Publication status	Published - 14 Jun 2023
MoE publication type	A1 Journal article-refereed

Bibliographical note

Publisher Copyright:
© 2023

Fields of Science

amyotrophic lateral sclerosis
case-control study
frontotemporal dementia
genome-wide association study
Lewy body dementia
non–Alzheimer's dementia
resource
structural variant
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology

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10.1016/j.xgen.2023.100316Licence: CC BY-NC-ND

1-s2.0-S2666979X23000848-mainFinal published version, 5.42 MBLicence: CC BY-NC-ND

Cite this

PROSPECT Consortium, The American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, Kaivola, K., Chia, R., Ding, J., Jansson, L., Laaksovirta, H., & Myllykangas, L. (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

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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 = "amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, Lewy body dementia, non–Alzheimer's dementia, resource, structural variant, 1182 Biochemistry, cell and molecular biology, 1184 Genetics, developmental biology, physiology",

author = "{PROSPECT Consortium} and {The American Genome Center} and {International LBD Genomics Consortium} and {International ALS/FTD Consortium} and 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 Patrick May and Lilja Jansson and Hannu Laaksovirta and Liisa Myllykangas and Tienari, {Pentti J.} and Miko Valori",

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",

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PROSPECT Consortium, The American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, Kaivola, K, Chia, R, Ding, J, Jansson, L , Laaksovirta, H & Myllykangas, L 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 - PROSPECT Consortium

AU - The American Genome Center

AU - International LBD Genomics Consortium

AU - International ALS/FTD Consortium

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 - May, Patrick

AU - Jansson, Lilja

AU - Laaksovirta, Hannu

AU - Myllykangas, Liisa

AU - Tienari, Pentti J.

AU - Valori, Miko

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 - amyotrophic lateral sclerosis

KW - case-control study

KW - frontotemporal dementia

KW - genome-wide association study

KW - Lewy body dementia

KW - non–Alzheimer's dementia

KW - resource

KW - structural variant

KW - 1182 Biochemistry, cell and molecular biology

KW - 1184 Genetics, developmental biology, physiology

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 -