Sex-specific genetic architecture of late-life memory performance

Jaclyn M. Eissman; Derek B. Archer; Shubhabrata Mukherjee; Michael L. Lee; Seo Eun Choi; Phoebe Scollard; Emily H. Trittschuh; Jesse B. Mez; William S. Bush; Brian W. Kunkle; Adam C. Naj; Katherine A. Gifford; Michael L. Cuccaro; Carlos Cruchaga; Margaret A. Pericak-Vance; Lindsay A. Farrer; Li San Wang; Gerard D. Schellenberg; Richard P. Mayeux; Jonathan L. Haines; Angela L. Jefferson; Walter A. Kukull; C. Dirk Keene; Andrew J. Saykin; Paul M. Thompson; Eden R. Martin; David A. Bennett; Lisa L. Barnes; Julie A. Schneider; Paul K. Crane; Timothy J. Hohman; Logan Dumitrescu

doi:10.1002/alz.13507

Sex-specific genetic architecture of late-life memory performance

Jaclyn M. Eissman, Derek B. Archer, Shubhabrata Mukherjee, Michael L. Lee, Seo Eun Choi, Phoebe Scollard, Emily H. Trittschuh, Jesse B. Mez, William S. Bush, Brian W. Kunkle, Adam C. Naj, Katherine A. Gifford, Michael L. Cuccaro, Carlos Cruchaga, Margaret A. Pericak-Vance, Lindsay A. Farrer, Li San Wang, Gerard D. Schellenberg, Richard P. Mayeux, Jonathan L. HainesAngela L. Jefferson, Walter A. Kukull, C. Dirk Keene, Andrew J. Saykin, Paul M. Thompson, Eden R. Martin, David A. Bennett, Lisa L. Barnes, Julie A. Schneider, Paul K. Crane, Timothy J. Hohman, Logan Dumitrescu

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

3 Scopus citations

Abstract

BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (N_males = 11,942; N_females = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

Original language	English
Pages (from-to)	1250-1267
Number of pages	18
Journal	Alzheimer's and Dementia
Volume	20
Issue number	2
DOIs	https://doi.org/10.1002/alz.13507
State	Published - Feb 2024

Keywords

Alzheimer's disease
GWAS
Genomics
aging
cognition
endophenotypes
memory
sex differences
sex-specific

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10.1002/alz.13507

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Eissman, J. M., Archer, D. B., Mukherjee, S., Lee, M. L., Choi, S. E., Scollard, P., Trittschuh, E. H., Mez, J. B., Bush, W. S., Kunkle, B. W., Naj, A. C., Gifford, K. A., Cuccaro, M. L., Cruchaga, C., Pericak-Vance, M. A., Farrer, L. A., Wang, L. S., Schellenberg, G. D., Mayeux, R. P., ... Dumitrescu, L. (2024). Sex-specific genetic architecture of late-life memory performance. Alzheimer's and Dementia, 20(2), 1250-1267. https://doi.org/10.1002/alz.13507

@article{1ccb4ebd4c2d446a94971b40aa6c9fbb,

title = "Sex-specific genetic architecture of late-life memory performance",

abstract = "BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.",

keywords = "Alzheimer's disease, GWAS, Genomics, aging, cognition, endophenotypes, memory, sex differences, sex-specific",

author = "Eissman, {Jaclyn M.} and Archer, {Derek B.} and Shubhabrata Mukherjee and Lee, {Michael L.} and Choi, {Seo Eun} and Phoebe Scollard and Trittschuh, {Emily H.} and Mez, {Jesse B.} and Bush, {William S.} and Kunkle, {Brian W.} and Naj, {Adam C.} and Gifford, {Katherine A.} and Cuccaro, {Michael L.} and Carlos Cruchaga and Pericak-Vance, {Margaret A.} and Farrer, {Lindsay A.} and Wang, {Li San} and Schellenberg, {Gerard D.} and Mayeux, {Richard P.} and Haines, {Jonathan L.} and Jefferson, {Angela L.} and Kukull, {Walter A.} and Keene, {C. Dirk} and Saykin, {Andrew J.} and Thompson, {Paul M.} and Martin, {Eden R.} and Bennett, {David A.} and Barnes, {Lisa L.} and Schneider, {Julie A.} and Crane, {Paul K.} and Hohman, {Timothy J.} and Logan Dumitrescu",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = feb,

doi = "10.1002/alz.13507",

language = "English",

volume = "20",

pages = "1250--1267",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

number = "2",

}

Eissman, JM, Archer, DB, Mukherjee, S, Lee, ML, Choi, SE, Scollard, P, Trittschuh, EH, Mez, JB, Bush, WS, Kunkle, BW, Naj, AC, Gifford, KA, Cuccaro, ML, Cruchaga, C, Pericak-Vance, MA, Farrer, LA, Wang, LS, Schellenberg, GD, Mayeux, RP, Haines, JL, Jefferson, AL, Kukull, WA, Keene, CD, Saykin, AJ, Thompson, PM, Martin, ER, Bennett, DA, Barnes, LL, Schneider, JA, Crane, PK, Hohman, TJ & Dumitrescu, L 2024, 'Sex-specific genetic architecture of late-life memory performance', Alzheimer's and Dementia, vol. 20, no. 2, pp. 1250-1267. https://doi.org/10.1002/alz.13507

TY - JOUR

T1 - Sex-specific genetic architecture of late-life memory performance

AU - Eissman, Jaclyn M.

AU - Archer, Derek B.

AU - Mukherjee, Shubhabrata

AU - Lee, Michael L.

AU - Choi, Seo Eun

AU - Scollard, Phoebe

AU - Trittschuh, Emily H.

AU - Mez, Jesse B.

AU - Bush, William S.

AU - Kunkle, Brian W.

AU - Naj, Adam C.

AU - Gifford, Katherine A.

AU - Cuccaro, Michael L.

AU - Cruchaga, Carlos

AU - Pericak-Vance, Margaret A.

AU - Farrer, Lindsay A.

AU - Wang, Li San

AU - Schellenberg, Gerard D.

AU - Mayeux, Richard P.

AU - Haines, Jonathan L.

AU - Jefferson, Angela L.

AU - Kukull, Walter A.

AU - Keene, C. Dirk

AU - Saykin, Andrew J.

AU - Thompson, Paul M.

AU - Martin, Eden R.

AU - Bennett, David A.

AU - Barnes, Lisa L.

AU - Schneider, Julie A.

AU - Crane, Paul K.

AU - Hohman, Timothy J.

AU - Dumitrescu, Logan

PY - 2024/2

Y1 - 2024/2

N2 - BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

AB - BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

KW - Alzheimer's disease

KW - GWAS

KW - Genomics

KW - aging

KW - cognition

KW - endophenotypes

KW - memory

KW - sex differences

KW - sex-specific

UR - http://www.scopus.com/inward/record.url?scp=85177228074&partnerID=8YFLogxK

U2 - 10.1002/alz.13507

DO - 10.1002/alz.13507

M3 - Article

C2 - 37984853

AN - SCOPUS:85177228074

SN - 1552-5260

VL - 20

SP - 1250

EP - 1267

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 2

ER -

Sex-specific genetic architecture of late-life memory performance

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