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Integrative genomic, transcriptomic, and proteomic analyses to investigate sex-specific differences in Alzheimer's Disease

Award Number: R01AG075827
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Integrative genomic, transcriptomic, and proteomic analyses to investigate sex-specific differences in Alzheimer's Disease - Alzheimer's disease (AD) affects 35 million people worldwide. However, there is no effective treatments to slow or halt the underlying neurodegeneration of AD. Strikingly, women are affected by AD about twice as much as men. Why women are disproportionately affected by AD is not well understood. Here, we hypothesize that there is an interaction between biological sex and brain gene expression that predisposes women to have a higher risk for AD. This hypothesis builds on our work investigating the genetic control of gene expression in the human brain. In those studies, we have identified genetic sites that are associated with variation in gene expression at the transcript and protein level in the human brain. Identifying genetic sites associated with natural variation in brain gene expression are incredibly useful to resolve genetic signals identified by genome-wide association study (GWAS) to specific causal transcripts and proteins. We have successfully used brain gene transcript and protein expression results with GWAS results to identify novel proteins for AD (Wingo et al, Nat Genet, 2021) and depression (Wingo et al, Nat Neurosci, 2021). These analyses implicate the causes of inherited genetic risk, which are presumably among the most important early contributors to disease, which make them highly relevant to resolving sex-specific disease risk. To test our hypothesis, we will first perform a sex-specific brain expression analysis for transcripts and proteins (Aim 1). To do this, we will leverage existing brain transcripts and protein expression data generated by national resources, and we propose a novel approach to cost-effectively increase the depth of proteomes to improve power. We expect to generate sex-specific quantitative trait loci (QTL) for brain transcripts (N=1655, 61% women) and proteins (N=1584, 66% women), and each gene will then be tested for evidence of interaction with sex. These results are likely to be of general interest to the neuroscience and genetics communities, and the data and results will be made widely available to the science community. In Aim 2, we will perform a sex-specific GWAS of AD, and we will identify genetic variants that interact with sex. To do this, we will perform sex-stratified GWAS using 1) case-control status for AD in participants from US studies (N=27,580), 2) AD-proxy case-control in participants from the UK Biobank (N=431,000), and iii) a meta- analysis of 1 and 2. In Aim 3, we will identify brain transcripts and proteins contributing to AD pathogenesis that are specific to men or women, respectively. To do this, we will integrate the sex-specific brain QTLs with the sex-specific GWAS results to resolve GWAS signals to proteins for women and men, separately. For AD genetic signals with evidence for sex interaction, we will test whether sex-specific gene expression accounts for the differences in AD risk between the sexes using causal inference approaches (e.g., Mendelian randomization). Findings from this project are highly likely to provide novel mechanistic insights into sex differences in AD and promising new targets for further sex-specific mechanistic and therapeutic studies of AD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $712,490 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	5	2/25/2026	NON-COMPETING CONTINUATION	$71,249
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	5	2/2/2026	NON-COMPETING CONTINUATION	$641,241
														Subtotal = $712,490

Issue Date FY: 2025 ( Subtotal = $756,545 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	4	3/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$688,507
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	002	4	6/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$68,038
2025	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	003	3	6/26/2025	NON-COMPETING CONTINUATION	$0
2025	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	3	3/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $756,545

Issue Date FY: 2024 ( Subtotal = $750,835 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	3	1/4/2024	NON-COMPETING CONTINUATION	$675,752
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	001	3	5/17/2024	NON-COMPETING CONTINUATION	$75,083
														Subtotal = $750,835

Issue Date FY: 2023 ( Subtotal = $750,835 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	2	1/18/2023	NON-COMPETING CONTINUATION	$750,835
														Subtotal = $750,835

Issue Date FY: 2022 ( Subtotal = $763,880 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	1	3/1/2022	NEW	$763,880
														Subtotal = $763,880

Grand Total All Awards = $3,734,585

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Integrative genomic, transcriptomic, and proteomic analyses to investigate sex-specific differences in Alzheimer's Disease

Award Number: R01AG075827

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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