Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease

被引：50

作者：

Eissman, Jaclyn M. ^{[1
,2
]}

Dumitrescu, Logan ^{[1
,2
]}

Mahoney, Emily R. ^{[1
,2
]}

Smith, Alexandra N. ^{[1
,2
]}

Mukherjee, Shubhabrata ^{[3
]}

Lee, Michael L. ^{[3
]}

Scollard, Phoebe ^{[3
]}

Choi, Seo Eun ^{[3
]}

Bush, William S. ^{[4
]}

Engelman, Corinne D. ^{[5
]}

Lu, Qiongshi ^{[6
,7
]}

Fardo, David W. ^{[8
,9
]}

Trittschuh, Emily H. ^{[10
,11
]}

Mez, Jesse ^{[12
]}

Kaczorowski, Catherine C. ^{[13
]}

Hernandez Saucedo, Hector ^{[14
]}

Widaman, Keith F. ^{[15
]}

Buckley, Rachel F. ^{[16
,17
,18
]}

Properzi, Michael J. ^{[16
]}

Mormino, Elizabeth C. ^{[19
]}

Yang, Hyun Sik ^{[16
,17
]}

Harrison, Theresa M. ^{[20
]}

Hedden, Trey ^{[21
]}

Nho, Kwangsik ^{[22
,23
]}

Andrews, Shea J. ^{[21
]}

Tommet, Douglas ^{[24
]}

Hadad, Niran ^{[13
]}

Sanders, R. Elizabeth ^{[3
]}

Ruderfer, Douglas M. ^{[2
]}

Gifford, Katherine A. ^{[1
]}

Zhong, Xiaoyuan ^{[6
,7
]}

Raghavan, Neha S. ^{[25
,26
,27
,28
]}

Vardarajan, Badri N. ^{[25
,26
,27
,28
]}

Pericak-Vance, Margaret A. ^{[29
]}

Farrer, Lindsay A. ^{[12
,30
,31
]}

Wang, Li San ^{[32
]}

Cruchaga, Carlos ^{[33
]}

Schellenberg, Gerard D. ^{[32
]}

Cox, Nancy J. ^{[2
]}

Haines, Jonathan L. ^{[4
]}

Keene, C. Dirk ^{[34
]}

Saykin, Andrew J. ^{[35
]}

Larson, Eric B. ^{[3
,36
]}

Sperling, Reisa A. ^{[16
]}

Mayeux, Richard ^{[25
,26
,27
,28
]}

Cuccaro, Michael L. ^{[29
]}

Bennett, David A. ^{[37
]}

Schneider, Julie A. ^{[37
]}

Crane, Paul K. ^{[3
]}

Jefferson, Angela L. ^{[1
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Memory & Alzheimers Ctr, 1207 17th Ave S, Nashville, TN 37212 USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

[3] Univ Washington, Dept Med, Seattle, WA USA

[4] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland Inst Computat Biol, Cleveland, OH 44106 USA

[5] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA

[6] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA

[7] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA

[8] Univ Kentucky, Dept Biostat, Coll Publ Hlth, Lexington, KY USA

[9] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY USA

[10] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[11] GRECC, VA Puget Sound Hlth Care Syst, Seattle, WA USA

[12] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[13] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA

[14] Univ Calif Davis, Med Ctr, Dept Neurol, UC Davis Alzheimers Dis Res Ctr, Sacramento, CA 95817 USA

[15] Univ Calif Riverside, Riverside, CA 92521 USA

[16] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA

[17] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimers Res & Treatment, Boston, MA 02115 USA

[18] Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic, Australia

[19] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[20] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA

[21] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[22] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA

[23] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA

[24] Brown Univ, Dept Psychiat & Human Behav, Sch Med, Providence, RI 02912 USA

[25] Columbia Univ, Dept Neurol, New York, NY USA

[26] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[27] Columbia Univ, Med Ctr, Inst Genom Med, New York, NY USA

[28] New York Presbyterian Hosp, New York, NY USA

[29] Univ Miami, Sch Med, John P Hussman Inst Human Genom, Miami, FL USA

[30] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[31] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA

[32] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Penn Neurodegenerat Genom Ctr, Philadelphia, PA USA

[33] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[34] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[35] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA

[36] Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA

[37] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

来源：

BRAIN | 2022年 / 145卷 / 07期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

Alzheimer's disease; sex differences; resilience; genetics; GWAS; HEART-RATE-VARIABILITY; APOLIPOPROTEIN-E GENOTYPE; X-CHROMOSOME; APOE; RISK; AGE; METAANALYSIS; COMPLEMENT; MENOPAUSE; VARIANTS;

D O I：

10.1093/brain/awac177

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, beta (females) = 0.08, P (females) = 5.76 x 10(-09), beta (males) = -0.01, P(males) = 0.70, beta (interaction) = 0.09, P (interaction) = 1.01 x 10(-04)] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context. By performing a series of sex-stratified and sex-interaction genetic analyses on continuous metrics of resilience to Alzheimer's disease pathology, Eissman et al. identify a genome-wide significant resilience locus in females and numerous molecular pathways that may contribute to resilience in each sex.

引用

页码：2541 / 2554

页数：14

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