Genetics of adipose cell-type expression and cardiometabolic traits

Active Project Grant Awarded Last action

Award ID
R01DK132775
Recipient
Awarding agency
Obligated
$3,579,424

Award facts

Completion date 90% complete
Originally
Place of performance
Los Angeles, CA 90095, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
A global obesity epidemic is driving the concomitant rapid increase in the prevalence of cardiometabolic disorders (cmds), including hypertriglyceridemia, type 2 diabetes (T2D), hypertension, and non-alcoholic fatty liver disease (nafld). Population- and SEX-specific differences in CMD predisposition exist; however, the biological mechanisms underlying these differences are not well understood. Previous large-scale genome-wide association studies (gwas) have reliably identified CMD-associated variants in multiple populations; however, functional understanding of the biological mechanisms of the gwas variants remains challenging. One major obstacle is the limited knowledge of the relevant cell types in which gwas variants affect gene expression. Bulk tissue gene expression data exist for CMD-relevant tissues, such as subcutaneous adipose, but these data exhibit considerable heterogeneity, including both cell type and cell state within each cell type. Subcutaneous adipose is an important human endocrine tissue for cmds, and IT is possible to collect high-quality adipose tissue samples from healthy individuals. However, the contributions of many adipose genes to cmds and CMD traits are still poorly understood. The current lack of cell-type expression reference data sets limits fine-scale regional transcriptional assessment of gwas variant effects. In addition, local expression quantitative trait locus (CIS- eqtl) analyses are confounded by cell-type-specific expression differences, which hamper replication efforts across independent bulk RNA-sequenced (RNA-SEQ) cohorts. To address these knowledge gaps and identify genetic effects on adipose cell-type gene expression, we will perform single nucleus RNA-sequencing (snrna- SEQ) in frozen subcutaneous adipose tissue biopsy samples from 300 well-characterized individuals, generate fine-scale estimates of cell-type proportions, identify study-wide and personalized cell-type-specific differences corresponding to cardiometabolic trait levels, and experimentally test gwas variants for allelic effects on cell- type-specific expression. We hypothesize that by elucidating adipose tissue cell-type expression from 300 existing frozen adipose biopsies, we can leverage available gwas and adipose bulk RNA-SEQ data (n=3,230; 45% female) from diverse populations to identify the relevant cell types for hundreds of CMD genes. In our preliminary studies, we have successfully performed snrna-SEQ in frozen human subcutaneous adipose tissue biopsies and performed multi-omic studies integrating gwas results with bulk adipose RNA-SEQ data, identifying hundreds of colocalized loci for CMD traits. Our approach will leverage the existing wealth of information available in gwas and bulk adipose RNA-SEQ cohorts to elucidate the largely unknown cell types of biological mechanisms in the adipose tissue that drive cmds. Success of the proposed study will substantially improve understanding of cell-type-specific transcriptional mechanisms of CMD diseases and traits in a key human metabolic tissue.

Transactions

Action Obligated Date
Amendment $0
Amendment $573,373
Amendment $573,373
Amendment $550,438
Amendment $607,155
Amendment $607,155
Amendment $0
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Original award $667,930
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Subawards

Subrecipient Amount Awarded
Ita-Suomen Yliopisto Drs. Paivi Pajukanta, Karen Mohlke and Laura Scott are proposing a research collaboration with Dr. Markku Laakso from the University of Eastern Finland, Kuopio,… $41,472
University Of North Carolina At Chapel Hill The University of North Carolina investigators will participate in snRNA data quality control and analyses, perform association analyses, eQTL discovery,… $645,293
Terveyden JA Hyvinvoinnin Laitos Sub to investigate the role of adipose cell-type specific expression in cardiometabolic disorders. For the current proposal, our mutual agreement is that the… $63,992
Regents Of The University Of Michigan The entire genomic and phenotypic data will be available for the key investigators. The adipose tissue sample were transferred to and are stored in Dr Francis… $619,348

Quick answers

Who received award R01DK132775?

R01DK132775 was awarded to University Of California, LOS Angeles by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on May 1, 2022.

How much is award R01DK132775 worth?

$3,579,424 has been obligated on R01DK132775.

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