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Genetic regulation of genes on active and inactive X chromosome and their contribution to sex-biased diseases

Award Number: F30GM151848
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Genetic regulation of genes on active and inactive X chromosome and their contribution to sex-biased diseases - PROJECT SUMMARY/ABSTRACT The human X chromosome has long been hypothesized to play a significant role in the etiology of sex-biased diseases and traits, particularly autoimmune diseases like lupus. Despite its importance, the X chromosome is largely understudied in genetic association and functional genomics studies. Such an omission is largely due to its unique biology. The hemizygosity of XY males necessitates XX females to achieve dosage compensation of X-linked genes by the means of X-chromosome inactivation (XCI). Thus, in females most genes are expressed only from the active X (Xa) and remain silent on the inactive X (Xi). However, up to 10% of genes consistently escape XCI in healthy females and are transcribed from both Xa and Xi. And 15-30% of genes variably escape XCI in a subset of females or tissues. We hypothesize such inter- and intra- individual heterogeneity is genetically influenced and disease relevant. However, the genetic architecture of X-linked genes and XCI escape remains poorly understood. We recently showed, for the first time, that XCI escape has significant heritability and variable XCI escape genes have a significantly increased enrichment of heritability in female-biased traits when compared to sex-balanced traits. Although promising, the annotations for XCI states were inferred only from lymphoblast cell lines, which could differ across human tissue/cell types. Recent works have shown disease heritability is enriched in regions surrounding genes specific to disease relevant tissues. Thus, matching each trait to relevant tissue/cell type specific XCI states in heritability analysis could pinpoint the disease and trait relevant tissue/cell types in which escape from XCI plays a significant role (Aim 1). To do so, we first propose an empirical bayes method to infer XCI escape states in an individual sample invariant of XCI mosaicism or presence of transcribed heterozygous SNPs in population scale bulk RNA-seq data. Unlike previous efforts, our method maximizes the samples and X-linked genes assayed to construct the most comprehensive XCI escape landscape across human tissue/cell types to date. Such a complete map will enable robust heritability estimation. Next, to understand the genetic influence on variable XCI escape, we propose a two-step method that accurately models XCI mosaicism and genetic regulation of Xa/Xi by jointly modeling male and female samples to detect associations with Xa and Xi expression levels (Xa-/Xi- QTL) (Aim 2). Our method offers substantial advancement and improves power to detect Xa-/Xi- QTLs compared to other approaches that 1) assume genetic regulation on Xa and Xi are largely similar or 2) attribute total expression of X-linked genes to expression from Xa and Xi. We will apply our approach across tissue/cell types and integrate the identified Xa-/Xi- QTL with existence genome wide association studies to identify tissue/cell type specific Xa and Xi gene and trait associations. We will apply our methods to some of the largest datasets for a variety of traits including lupus, diabetes, and addiction. Overall, our proposed methods will allow comprehensive assessment of the role the X chromosome and XCI escape plays in the etiology of diseases and traits, particularly those that are sex-biased like autoimmune 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 = $0 )
2026	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	2	6/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $34,800 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	2	8/19/2024	NON-COMPETING CONTINUATION	$34,800
														Subtotal = $34,800

Issue Date FY: 2023 ( Subtotal = $34,621 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	1	8/3/2023	NEW	$0
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	1	8/3/2023	NEW	$34,621
														Subtotal = $34,621

Grand Total All Awards = $69,421

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Genetic regulation of genes on active and inactive X chromosome and their contribution to sex-biased diseases

Award Number: F30GM151848

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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