Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

Alireza Nazarian; Yury Loika; Liang He; Irina Culminskaya; Alexander M. Kulminski

doi:10.1002/alz.12540

Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

Alireza Nazarian
, Yury Loika
, Liang He
, Irina Culminskaya
, Alexander M. Kulminski^*

^*Kontaktforfatter

Duke University

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Abstract

Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants. Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status. Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function. Discussion: These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.

Originalsprog	Engelsk
Tidsskrift	Alzheimer's & Dementia
Vol/bind	18
Udgave nummer	11
Sider (fra-til)	2067-2078
ISSN	1552-5260
DOI	https://doi.org/10.1002/alz.12540
Status	Udgivet - nov. 2022
Udgivet eksternt	Ja

Bibliografisk note

Funding Information:
This research was supported by grants from the National Institute on Aging (P01AG043352, R01AG047310, R01AG061853, R01AG065477, and R01AG070488). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This manuscript was prepared using limited access datasets obtained from dbGaP (accession numbers: phs000372.v1.p1 [ADGC], phs000572.v8.p4 [ADSP], phs000287.v5.p1 [CHS], phs000007.v28.p10 [FHS], and phs000168.v2.p2 [LOAD FBS]) and NIAGADS (accession number: NG00067 [ADSP]). Please also see the Supporting Acknowledgment in the supporting information regarding these five datasets.

Publisher Copyright:
© 2021 the Alzheimer's Association

Finansiering

This research was supported by grants from the National Institute on Aging (P01AG043352, R01AG047310, R01AG061853, R01AG065477, and R01AG070488). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This manuscript was prepared using limited access datasets obtained from dbGaP (accession numbers: phs000372.v1.p1 [ADGC], phs000572.v8.p4 [ADSP], phs000287.v5.p1 [CHS], phs000007.v28.p10 [FHS], and phs000168.v2.p2 [LOAD FBS]) and NIAGADS (accession number: NG00067 [ADSP]). Please also see the Supporting Acknowledgment in the supporting information regarding these five datasets.

Dokumenter og links

10.1002/alz.12540

SDU link

Tjek adgangen til materialet i Syddansk Universitetsbiblioteks søgemaskine

Citationsformater

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title = "Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk",

abstract = "Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants. Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status. Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function. Discussion: These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.",

keywords = "Alleles, Alzheimer Disease/genetics, Apolipoprotein E2/genetics, Apolipoprotein E4/genetics, Apolipoproteins E/genetics, Genotype, Humans",

author = "Alireza Nazarian and Yury Loika and Liang He and Irina Culminskaya and Kulminski, \{Alexander M.\}",

note = "Funding Information: This research was supported by grants from the National Institute on Aging (P01AG043352, R01AG047310, R01AG061853, R01AG065477, and R01AG070488). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This manuscript was prepared using limited access datasets obtained from dbGaP (accession numbers: phs000372.v1.p1 [ADGC], phs000572.v8.p4 [ADSP], phs000287.v5.p1 [CHS], phs000007.v28.p10 [FHS], and phs000168.v2.p2 [LOAD FBS]) and NIAGADS (accession number: NG00067 [ADSP]). Please also see the Supporting Acknowledgment in the supporting information regarding these five datasets. Publisher Copyright: {\textcopyright} 2021 the Alzheimer's Association",

year = "2022",

month = nov,

doi = "10.1002/alz.12540",

language = "English",

volume = "18",

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TY - JOUR

T1 - Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

AU - Nazarian, Alireza

AU - Loika, Yury

AU - He, Liang

AU - Culminskaya, Irina

AU - Kulminski, Alexander M.

N1 - Funding Information: This research was supported by grants from the National Institute on Aging (P01AG043352, R01AG047310, R01AG061853, R01AG065477, and R01AG070488). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This manuscript was prepared using limited access datasets obtained from dbGaP (accession numbers: phs000372.v1.p1 [ADGC], phs000572.v8.p4 [ADSP], phs000287.v5.p1 [CHS], phs000007.v28.p10 [FHS], and phs000168.v2.p2 [LOAD FBS]) and NIAGADS (accession number: NG00067 [ADSP]). Please also see the Supporting Acknowledgment in the supporting information regarding these five datasets. Publisher Copyright: © 2021 the Alzheimer's Association

PY - 2022/11

Y1 - 2022/11

N2 - Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants. Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status. Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function. Discussion: These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.

AB - Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants. Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status. Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function. Discussion: These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.

KW - Alleles

KW - Alzheimer Disease/genetics

KW - Apolipoprotein E2/genetics

KW - Apolipoprotein E4/genetics

KW - Apolipoproteins E/genetics

KW - Genotype

KW - Humans

U2 - 10.1002/alz.12540

DO - 10.1002/alz.12540

M3 - Journal article

C2 - 34978151

AN - SCOPUS:85122156674

SN - 1552-5260

VL - 18

SP - 2067

EP - 2078

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 11

ER -

Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

Abstract

Bibliografisk note

Finansiering

Dokumenter og links

SDU link

Fingeraftryk

Citationsformater