Cargando…

Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects

Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer’s disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer’s Disease Sequ...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Hui, Dombroski, Beth A, Cheng, Po-Liang, Tucci, Albert, Si, Ya-Qin, Farrell, John J, Tzeng, Jung-Ying, Leung, Yuk Yee, Malamon, John S, Wang, Li-San, Vardarajan, Badri N, Farrer, Lindsay A, Schellenberg, Gerard D, Lee, Wan-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516060/
https://www.ncbi.nlm.nih.gov/pubmed/37745545
http://dx.doi.org/10.1101/2023.09.13.23295505
_version_ 1785109064422785024
author Wang, Hui
Dombroski, Beth A
Cheng, Po-Liang
Tucci, Albert
Si, Ya-Qin
Farrell, John J
Tzeng, Jung-Ying
Leung, Yuk Yee
Malamon, John S
Wang, Li-San
Vardarajan, Badri N
Farrer, Lindsay A
Schellenberg, Gerard D
Lee, Wan-Ping
author_facet Wang, Hui
Dombroski, Beth A
Cheng, Po-Liang
Tucci, Albert
Si, Ya-Qin
Farrell, John J
Tzeng, Jung-Ying
Leung, Yuk Yee
Malamon, John S
Wang, Li-San
Vardarajan, Badri N
Farrer, Lindsay A
Schellenberg, Gerard D
Lee, Wan-Ping
author_sort Wang, Hui
collection PubMed
description Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer’s disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, P=0.03), particularly for singletons (OR=1.12, P=0.0002) and homozygous events (OR=1.10, P<0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1, were associated with AD (SKAT-O P=0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R(2)=0.99) with rs143080277 (chr2:105749599) in NCK2. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.
format Online
Article
Text
id pubmed-10516060
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-105160602023-09-23 Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects Wang, Hui Dombroski, Beth A Cheng, Po-Liang Tucci, Albert Si, Ya-Qin Farrell, John J Tzeng, Jung-Ying Leung, Yuk Yee Malamon, John S Wang, Li-San Vardarajan, Badri N Farrer, Lindsay A Schellenberg, Gerard D Lee, Wan-Ping medRxiv Article Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer’s disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, P=0.03), particularly for singletons (OR=1.12, P=0.0002) and homozygous events (OR=1.10, P<0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1, were associated with AD (SKAT-O P=0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R(2)=0.99) with rs143080277 (chr2:105749599) in NCK2. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics. Cold Spring Harbor Laboratory 2023-09-13 /pmc/articles/PMC10516060/ /pubmed/37745545 http://dx.doi.org/10.1101/2023.09.13.23295505 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Wang, Hui
Dombroski, Beth A
Cheng, Po-Liang
Tucci, Albert
Si, Ya-Qin
Farrell, John J
Tzeng, Jung-Ying
Leung, Yuk Yee
Malamon, John S
Wang, Li-San
Vardarajan, Badri N
Farrer, Lindsay A
Schellenberg, Gerard D
Lee, Wan-Ping
Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
title Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
title_full Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
title_fullStr Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
title_full_unstemmed Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
title_short Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
title_sort structural variation detection and association analysis of whole-genome-sequence data from 16,905 alzheimer’s diseases sequencing project subjects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516060/
https://www.ncbi.nlm.nih.gov/pubmed/37745545
http://dx.doi.org/10.1101/2023.09.13.23295505
work_keys_str_mv AT wanghui structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT dombroskibetha structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT chengpoliang structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT tuccialbert structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT siyaqin structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT farrelljohnj structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT tzengjungying structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT leungyukyee structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT malamonjohns structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT wanglisan structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT vardarajanbadrin structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT farrerlindsaya structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT schellenberggerardd structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects
AT leewanping structuralvariationdetectionandassociationanalysisofwholegenomesequencedatafrom16905alzheimersdiseasessequencingprojectsubjects