RNASE6 is a novel modifier of APOE-ε4 effects on cognition

Mabel Seto; Rebecca L. Weiner; Logan Dumitrescu; Emily R. Mahoney; Shania L. Hansen; Vaibhav Janve; Omair A. Khan; Dandan Liu; Yanling Wang; Vilas Menon; Philip L. de Jager; Julie A. Schneider; David A. Bennett; Katherine A. Gifford; Angela L. Jefferson; Timothy J. Hohman

doi:10.1016/j.neurobiolaging.2022.06.011

RNASE6 is a novel modifier of APOE-ε4 effects on cognition

Mabel Seto, Rebecca L. Weiner, Logan Dumitrescu, Emily R. Mahoney, Shania L. Hansen, Vaibhav Janve, Omair A. Khan, Dandan Liu, Yanling Wang, Vilas Menon, Philip L. de Jager, Julie A. Schneider, David A. Bennett, Katherine A. Gifford, Angela L. Jefferson, Timothy J. Hohman^*

^*Corresponding author for this work

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

Abstract

Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10−8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.

Original language	English
Pages (from-to)	66-76
Number of pages	11
Journal	Neurobiology of Aging
Volume	118
DOIs	https://doi.org/10.1016/j.neurobiolaging.2022.06.011
Publication status	Published - 1 Oct 2022
Externally published	Yes

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10.1016/j.neurobiolaging.2022.06.011

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Seto, M., Weiner, R. L., Dumitrescu, L., Mahoney, E. R., Hansen, S. L., Janve, V., Khan, O. A., Liu, D., Wang, Y., Menon, V., de Jager, P. L., Schneider, J. A., Bennett, D. A., Gifford, K. A., Jefferson, A. L., & Hohman, T. J. (2022). RNASE6 is a novel modifier of APOE-ε4 effects on cognition. Neurobiology of Aging, 118, 66-76. https://doi.org/10.1016/j.neurobiolaging.2022.06.011

@article{6ebd68ad88cb4f0cbb09ab62fcd5596f,

title = "RNASE6 is a novel modifier of APOE-ε4 effects on cognition",

abstract = "Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10−8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.",

keywords = "Alzheimer's, Blood, Brain, Cognition, Gene expression",

author = "Mabel Seto and Weiner, {Rebecca L.} and Logan Dumitrescu and Mahoney, {Emily R.} and Hansen, {Shania L.} and Vaibhav Janve and Khan, {Omair A.} and Dandan Liu and Yanling Wang and Vilas Menon and {de Jager}, {Philip L.} and Schneider, {Julie A.} and Bennett, {David A.} and Gifford, {Katherine A.} and Jefferson, {Angela L.} and Hohman, {Timothy J.}",

note = "Funding Information: This research was supported in part by grants K01AG049164, K24AG046373, R21AG059941, R01AG059716, R01AG034962, R01HL111516, R01NS100980, R01AG056534, RF1AG15819 from the Intramural Research Program, the National Institute on Aging, the National Institutes of Health, the Vanderbilt University Advanced Computing Center for Research and Education (ACCRE) instrumentation grant (S10OD023680), the Vanderbilt Institute for Clinical and Translational Research (VICTR) grant (UL1TR000445, UL1TR002243), and the Vanderbilt Memory & Alzheimer's Center. Additional study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG010161 (ROS), R01AG015819 (ROSMAP; genomics and RNAseq), R01AG017917 (MAP), R01AG030146, R01AG036042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG036836 (RNAseq), R01AG408015 (monocyte RNAseq) RF1AG057473 (single nucleus RNAseq), U01AG032984 (genomic and whole exome sequencing), U01AG046152 (ROSMAP AMP-AD, targeted proteomics), U01AG046161 (TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu. The results published here are in whole or in part based on data obtained from Agora and the AD Knowledge Portal (https://adknowledgeportal.org), which are supported by the NIA-funded AMP-AD consortium that shares evidence in support of AD target discovery. The authors have not published or posted any related papers from the study described in this manuscript, and this manuscript is not under review at any other journal. We have presented preliminary work for this project at the Alzheimer's Association International Conference in July of 2021. All authors have substantially contributed to this project and have provided approval for submission. Funding Information: This research was supported in part by grants K01AG049164, K24AG046373, R21AG059941, R01AG059716, R01AG034962, R01HL111516, R01NS100980, R01AG056534, RF1AG15819 from the Intramural Research Program, the National Institute on Aging, the National Institutes of Health, the Vanderbilt University Advanced Computing Center for Research and Education (ACCRE) instrumentation grant (S10OD023680), the Vanderbilt Institute for Clinical and Translational Research (VICTR) grant (UL1TR000445, UL1TR002243), and the Vanderbilt Memory & Alzheimer's Center. Funding Information: Additional study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG010161 (ROS), R01AG015819 (ROSMAP; genomics and RNAseq), R01AG017917 (MAP), R01AG030146, R01AG036042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG036836 (RNAseq), R01AG408015 (monocyte RNAseq) RF1AG057473 (single nucleus RNAseq), U01AG032984 (genomic and whole exome sequencing), U01AG046152 (ROSMAP AMP-AD, targeted proteomics), U01AG046161 (TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu . Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = oct,

day = "1",

doi = "10.1016/j.neurobiolaging.2022.06.011",

language = "English",

volume = "118",

pages = "66--76",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - RNASE6 is a novel modifier of APOE-ε4 effects on cognition

AU - Seto, Mabel

AU - Weiner, Rebecca L.

AU - Dumitrescu, Logan

AU - Mahoney, Emily R.

AU - Hansen, Shania L.

AU - Janve, Vaibhav

AU - Khan, Omair A.

AU - Liu, Dandan

AU - Wang, Yanling

AU - Menon, Vilas

AU - de Jager, Philip L.

AU - Schneider, Julie A.

AU - Bennett, David A.

AU - Gifford, Katherine A.

AU - Jefferson, Angela L.

AU - Hohman, Timothy J.

N1 - Funding Information: This research was supported in part by grants K01AG049164, K24AG046373, R21AG059941, R01AG059716, R01AG034962, R01HL111516, R01NS100980, R01AG056534, RF1AG15819 from the Intramural Research Program, the National Institute on Aging, the National Institutes of Health, the Vanderbilt University Advanced Computing Center for Research and Education (ACCRE) instrumentation grant (S10OD023680), the Vanderbilt Institute for Clinical and Translational Research (VICTR) grant (UL1TR000445, UL1TR002243), and the Vanderbilt Memory & Alzheimer's Center. Additional study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG010161 (ROS), R01AG015819 (ROSMAP; genomics and RNAseq), R01AG017917 (MAP), R01AG030146, R01AG036042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG036836 (RNAseq), R01AG408015 (monocyte RNAseq) RF1AG057473 (single nucleus RNAseq), U01AG032984 (genomic and whole exome sequencing), U01AG046152 (ROSMAP AMP-AD, targeted proteomics), U01AG046161 (TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu. The results published here are in whole or in part based on data obtained from Agora and the AD Knowledge Portal (https://adknowledgeportal.org), which are supported by the NIA-funded AMP-AD consortium that shares evidence in support of AD target discovery. The authors have not published or posted any related papers from the study described in this manuscript, and this manuscript is not under review at any other journal. We have presented preliminary work for this project at the Alzheimer's Association International Conference in July of 2021. All authors have substantially contributed to this project and have provided approval for submission. Funding Information: This research was supported in part by grants K01AG049164, K24AG046373, R21AG059941, R01AG059716, R01AG034962, R01HL111516, R01NS100980, R01AG056534, RF1AG15819 from the Intramural Research Program, the National Institute on Aging, the National Institutes of Health, the Vanderbilt University Advanced Computing Center for Research and Education (ACCRE) instrumentation grant (S10OD023680), the Vanderbilt Institute for Clinical and Translational Research (VICTR) grant (UL1TR000445, UL1TR002243), and the Vanderbilt Memory & Alzheimer's Center. Funding Information: Additional study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG010161 (ROS), R01AG015819 (ROSMAP; genomics and RNAseq), R01AG017917 (MAP), R01AG030146, R01AG036042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG036836 (RNAseq), R01AG408015 (monocyte RNAseq) RF1AG057473 (single nucleus RNAseq), U01AG032984 (genomic and whole exome sequencing), U01AG046152 (ROSMAP AMP-AD, targeted proteomics), U01AG046161 (TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu . Publisher Copyright: © 2022

PY - 2022/10/1

Y1 - 2022/10/1

N2 - Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10−8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.

AB - Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10−8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.

KW - Alzheimer's

KW - Blood

KW - Brain

KW - Cognition

KW - Gene expression

UR - http://www.scopus.com/inward/record.url?scp=85134809473&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2022.06.011

DO - 10.1016/j.neurobiolaging.2022.06.011

M3 - Article

C2 - 35896049

SN - 0197-4580

VL - 118

SP - 66

EP - 76

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

RNASE6 is a novel modifier of APOE-ε4 effects on cognition

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