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Linking microbiome genetic variants with cardiovascular phenotypes in 50,000 individuals

Award Number: R01HL160862
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Linking microbiome genetic variants with cardiovascular phenotypes in 50,000 individuals - PROJECT SUMMARY / ABSTRACT The human body is home to a complex community of microorganisms (“microbiome”) that differs in composition between people, with numerous correlates to cardiovascular disease (CVD). Any two people will harbor different strains of a given species, which can be more genetically different than a human and chimpanzee with <60% of their genes shared. Even within a single person, each microbiome species may be a complex mixture of strains with different genomes and functional capabilities. This striking within-species genetic diversity has functional consequences for CVD, because gene loss and gain modify how strains process our diet, metabolize drugs, and stimulate inflammation. Hence, a population genetic approach is essential for revealing causal links between the microbiome and CVD. We have compiled a deeply phenotyped cohort of ~50,000 individuals with metagenomic sequencing of their gut microbiomes. This dataset includes ~8,000 people with atherosclerosis, thousands with measurements of heart function and metabolic health, and hundreds with acute coronary syndrome. This cohort is a unique and ideal setting to perform a well-powered CVD metagenome-wide association study (MWAS). Several barriers must be overcome before MWAS can be deployed at this scale. First, we must reduce the infeasible computational cost of genotyping thousands of microbiome species across ~50,000 people. Second, to ensure that statistical tests for associations do not have high false positive rates we need statistical models that adjust for microbial population structure within and across hosts. The goal of this proposal is to create a research toolbox to address these challenges as well as to identify putative mechanistic links between microbiome and CVD. We will develop data structures and query algorithms for accelerated genotype estimation and mixed effects models for accurate association tests. All code and methods will be open source and designed to be easily extended to other microbiome cohorts. Applying these tools to our cohort, we aim to identify specific microbial genes and pathways responsible for known associations between microbes and CVD. We also expect to discover new associations that were missed because cohorts were too small or they were analyzed with methods that ignore differences in gene content across strains. These findings will be used to identify microbial biomarkers for CVD diagnosis and personalized treatments or to design microbiome targeted drugs, prebiotics, and probiotics to treat heart disease.


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 = $0 )
2026	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	4	3/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $685,007 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	4	8/7/2025	NON-COMPETING CONTINUATION	$685,007
														Subtotal = $685,007

Issue Date FY: 2024 ( Subtotal = $671,307 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	3	6/20/2024	NON-COMPETING CONTINUATION	$671,307
														Subtotal = $671,307

Issue Date FY: 2023 ( Subtotal = $685,007 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	2	6/16/2023	NON-COMPETING CONTINUATION	$685,007
														Subtotal = $685,007

Issue Date FY: 2022 ( Subtotal = $707,257 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	1	7/27/2022	NEW	$707,257
														Subtotal = $707,257

Grand Total All Awards = $2,748,578

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Linking microbiome genetic variants with cardiovascular phenotypes in 50,000 individuals

Award Number: R01HL160862

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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