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Machine Learning for Decoding the Genetic Architecture of Complex Traits and Diseases Across Populations

Award Number: R35GM127063
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Machine Learning for Decoding the Genetic Architecture of Complex Traits and Diseases Across Populations - Unraveling the genetic basis of complex traits is a crucial step toward advancing human genetics and precision medicine. Despite significant progress, gaps remain in the molecular mechanisms underlying GWAS findings. My group has developed novel statistical and computational approaches for post-GWAS functional characterization and for individualized genetic risk assessment. These methods facilitate the systematic characterization of the genetic architecture underlying phenotypic variation, with a strategic emphasis on improving biological resolution and statistical generalizability. In parallel, we have developed and applied statistical tools to uncover regulators of human proteomic variation, generating one of the most comprehensive catalogs of protein quantitative trait loci (pQTL) in non-disease human tissues. Beyond providing novel insights on regulatory mechanisms, these pQTLs point to plausible genes and functions underlying complex trait GWAS associations that elude other omics analyses, such as eQTLs. Our long-term goal is to decode complex traits at molecular, individual, and population levels. The field of human complex trait genetics is entering a transformative era, fueled by advances in biobank-scale population cohorts, precise single-cell technologies, and revolutionary AI/ML tools. Inspired by these developments and building upon our expertise, we propose three innovative directions: (1) generating cell type-specific proteomic profiles by computational deconvolution of tissue-level data, thereby addressing experimental limitations in single-cell proteomics; (2) developing protein-prediction models informed by regulatory landscapes to enhance proteome-wide association studies (PWAS); and (3) constructing AI-assisted polygenic risk scores (PRS) that leverage biobank cohorts and capture complex allele interactions, producing generalizable and individualized PRS. Methodological innovation lies in the adaptive integration of heterogeneous data, while conceptual innovation incorporates biological insights into AI/ML-driven models. By leveraging emerging resources and computational advancements, the proposed research offers exciting opportunities for scientific discoveries that ultimately enhance clinical utility and precision health models across complex diseases.


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 = $423,500 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	6	3/6/2026	COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	11/5/2024	NON-COMPETING CONTINUATION	$0
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	5/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	4/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $353,250 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	7/19/2022	NON-COMPETING CONTINUATION	$35,326
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	4/1/2022	NON-COMPETING CONTINUATION	$317,924
														Subtotal = $353,250

Issue Date FY: 2021 ( Subtotal = $353,250 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	3/24/2021	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2020 ( Subtotal = $353,250 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	3/26/2020	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2019 ( Subtotal = $353,250 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	3/27/2019	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2018 ( Subtotal = $353,250 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	3/27/2018	NEW	$353,250
														Subtotal = $353,250

Grand Total All Awards = $2,189,750

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Machine Learning for Decoding the Genetic Architecture of Complex Traits and Diseases Across Populations

Award Number: R35GM127063

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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