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A paradigm for comprehensive genetic association studies of complex disease using pangenomic methods and local ancestry inference

Award Number: R01HG013371
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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A paradigm for comprehensive genetic association studies of complex disease using pangenomic methods and local ancestry inference - The overarching goal of this proposal is to develop a paradigm for comprehensive whole genome sequencing (WGS) studies of complex genetic diseases and traits by leveraging new approaches for variant analysis and trait association, and to use these methods for improving disease and trait mapping studies, using coronary artery disease as a prototypical example. We will first build a new WGS variant analysis pipeline based on methods that leverage a population of fully assembled reference genomes (a “pangenome”), rather than a single linear reference genome (e.g. GRCh38). By employing variation-aware approaches to read alignment and genotyping, these next-generation methods promise to greatly improve variant detection performance and to alleviate the bias that plagues the current generation of methods. Our pipeline will be designed to detect all forms of variation, including single nucleotide variants, small indels, structural variation, and tandem repeat length variation, and will be constructed based on systematic benchmarking of candidate methods from our labs and the broader community. We will then use these methods in combination with haplotype-aware trait association approaches to study the complex genetic basis of coronary artery disease and cardiometabolic risk factors in a set of ~55,000 deeply sequenced human genomes generated by the Centers for Common Disease Genomics (CCDG). We will assess the contribution of all variant types to coronary artery disease and complex coronary disease risk factors and quantify the improvements in gene mapping studies of common disease that are possible using new pangenomic analysis methods. We will leverage patterns of haplotypic admixture, using a novel tree-based haplotype association method to fine map novel and known coronary artery disease and risk factor loci, and to identify loci where local haplotypic origin modulates risk of coronary disease and risk factors. Finally, we will extend this work to a much larger set of individuals and traits by applying our methods to WGS data from public biobanks allowing us to more broadly assess the role of complex genome variation in human diseases and complex traits. Taken together, this work will yield valuable new methods and data resources for the community, will help pave the way to improve the next generation of human disease gene mapping studies by using pangenomic approaches, and has the potential to yield new insight into the genetic basis of coronary artery 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 = $711,447 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	000	3	12/23/2025	NON-COMPETING CONTINUATION	$711,447
														Subtotal = $711,447

Issue Date FY: 2025 ( Subtotal = $711,447 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	000	2	3/11/2025	NON-COMPETING CONTINUATION	$640,303
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	001	2	4/25/2025	NON-COMPETING CONTINUATION	$71,144
														Subtotal = $711,447

Issue Date FY: 2024 ( Subtotal = $726,330 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	000	1	1/10/2024	NEW	$660,491
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	001	1	8/5/2024	NEW	$65,839
														Subtotal = $726,330

Grand Total All Awards = $2,149,224

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A paradigm for comprehensive genetic association studies of complex disease using pangenomic methods and local ancestry inference

Award Number: R01HG013371

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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