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; Alzheimer's Disease Neuroimaging Initiative (ADNI) | Alzheimer's Disease Genetics Consortium (ADGC) | The Alzheimer's Disease Sequencing Project (ADSP); 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

Alzheimers Dement. 2024 Feb;20(2):1250-1267. doi: 10.1002/alz.13507. Epub 2023 Nov 20.

Authors

Jaclyn M Eissman^{1

2}, Derek B Archer^{1

2}, Shubhabrata Mukherjee³, Michael L Lee³, Seo-Eun Choi³, Phoebe Scollard³, Emily H Trittschuh^{4

5}, Jesse B Mez⁶, William S Bush⁷, Brian W Kunkle⁸, Adam C Naj^{9

10}, Katherine A Gifford¹; Alzheimer's Disease Neuroimaging Initiative (ADNI) | Alzheimer's Disease Genetics Consortium (ADGC) | The Alzheimer's Disease Sequencing Project (ADSP); Michael L Cuccaro⁸, Carlos Cruchaga^{11

12}, Margaret A Pericak-Vance⁸, Lindsay A Farrer^{6

13

14}, Li-San Wang¹⁰, Gerard D Schellenberg¹⁰, Richard P Mayeux^{15

16

17}, Jonathan L Haines⁷, Angela L Jefferson¹, Walter A Kukull¹⁸, C Dirk Keene¹⁹, Andrew J Saykin^{20

21}, Paul M Thompson²², Eden R Martin⁸, David A Bennett²³, Lisa L Barnes²³, Julie A Schneider²³, Paul K Crane³, Timothy J Hohman^{1

2}, Logan Dumitrescu^{1

2}

Affiliations

¹ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Department of Medicine, University of Washington, Seattle, Washington, USA.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ VA Puget Sound Health Care System, GRECC, Seattle, Washington, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
⁷ Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
⁸ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁹ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁰ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹¹ Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA.
¹² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, Missouri, USA.
¹³ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
¹⁴ Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
¹⁵ Columbia University, New York, New York, USA.
¹⁶ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, New York, USA.
¹⁷ The Institute for Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, New York, USA.
¹⁸ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
²⁰ Department of Radiology and Imaging Services, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²¹ Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
²² Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

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.

Keywords: Alzheimer's disease; GWAS; Genomics; aging; cognition; endophenotypes; memory; sex differences; sex-specific.

MeSH terms

Alzheimer Disease* / genetics
Cognition
Cognitive Aging*
Female
Genome-Wide Association Study
Humans
Male
Sex Characteristics

Abstract

MeSH terms

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