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Principal Investigator: Alisa Knodle Manning
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $709,961
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Type 2 diabetes continues to spread globally due to unhealthy environment interacting with genetics. Recent genetic
discoveries of >700 variants at >400 loci associated with type 2 diabetes (T2D) and its related quantitative traits (QTs:
fasting glucose (FG), insulin (FI) and hemoglobin A1c (A1c)) give insight into new T2D pathobiology. However, most
discoveries have been in whites; studies in minority groups disproportionately affected by T2D are needed. Also, most
associations are in the non-coding genome, indicating that whole genome sequence (WGS) analysis is needed for full
variant and effector gene characterization. The NHLBI Trans-Omics for Precision Medicine (TOPMed) study includes
WGS from 21,493 cases of prevalent T2D and 63,541 controls from five populations (41,557 Euro, 23,203 AA, 16,213
Latino, 2,867 Asian, 1,194 Samoan Adiposity Study) from 28 cohorts and up to 54,407 non-T2D individuals with FG,
FI or HbA1c, as well as age of T2D onset, level of glycemic control and longitudinal follow-up for incident T2D
events. In this project Aim 1 is to test WGS-wide in five ancestry groups for known and new common and rare variants
associated T2D and QTs. We will conduct analyses in the NHLBI BioData Catalyst. Replication of novel variants is
available in >1 million individuals of diverse ancestry from six biobanks with T2D (UKBB, BioME, BioVU, Partners
BB, REGARDS, MVP) with TOPMed-imputed genomic array data. For health translation, we will group T2D genetic
risk variants into polygenic risk scores (PRSs) that predict future T2D or characterize specific physiological axes, and
use variants in Mendelian Randomization (MR) tests of disease causality. Next, TOPMed has blood omic measures
from five ancestry groups that may also identify novel biological networks relevant to T2D pathobiology, including
whole blood DNA methylation (measured by sequencing or microarrays, N=11,131), transcriptomics (RNA-seq)
(N=8,334), proteomics (SomaLogic aptamers or Olink proteomics, N=7,897) and metabolomics (liquid
chromatography/mass spectroscopy, N=11,631). In Aim 2, we will test omic signatures associated with T2D and QTs
individually and in multidimensional omic and genomic network models of the pathobiology of T2D. Finally, in Aim 3
we plan to integrate TOPMed WGS and omic results with bespoke cell or tissue-specific (beta cell, islet, liver, fat and
muscle) omic and epigenomic annotation (ATAC-seq, RNA-seq, Hi-C, ChIP-seq) in the Accelerating Medicine
Partnership (AMP) T2D Diabetes epiGenome Atlas, and with hundreds of additional genomic trait associations in the
AMP T2D Knowledge Portal (T2DKP) for ‘in silico variant-to-function’ and phenomic studies. Complete functional
mapping with blood and tissue-specific omic integration of the human T2D and QT genome is on the horizon. Our
multidisciplinary, multicenter team has a proven track record in genetics and omic discovery. We are actively working
with TOPMed, AMP T2D DGA and T2DKP data. We are well positioned to achieve the Aims of the proposal, with the
intention to find new approaches to address the global epidemic of T2D in all populations at risk.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Acceleration><Active Follow-up><Address><Adult-Onset Diabetes Mellitus><Affect><African American><Afro American><Afroamerican><Age><Allele Frequency><Alleles><Allelomorphs><Asian><Assay for Transposase-Accessible Chromatin using sequencing><Atlases><Beta Cell><Bio-Informatics><Bioinformatics><Biological><Biological Markers><Biology><Blood><Blood Reticuloendothelial System><Body Tissues><Causality><Cell Body><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Clinical Data><Code><Coding System><Collaborations><Cross-Product Ratio><DNA Methylation><Data><Death><Development><Diabetes Mellitus><Dimensions><Disease><Disorder><East Asian><Environment><Epidemic><Etiology><European><Event><Fats><Fatty acid glycerol esters><Functional RNA><Future><GWA study><GWAS><Gene Frequency><Gene variant><Genes><Genetic><Genetic Risk><Genome><Genomics><Glycohemoglobin A><Glycosylated hemoglobin A><Goals><Groups at risk><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Health><Hemoglobin><Hemoglobin A(1)><Hepatic><Hi-C><Hispanic><Human><Humulin R><Individual><Individuals from minority><Individuals of minority><Insulin><Insulin Cell><Insulin Resistance><Insulin Secreting Cell><Intention><Ketosis-Resistant Diabetes Mellitus><Knowledge><Knowledge Portal><Knowledge base Portal><Knowledgebase Portal><Latino><Lead><Liver><Maps><Maturity-Onset Diabetes Mellitus><Measures><Medicine><Mendelian randomization><Methods><Minor><Minority Groups><Minority People><Minority Population><Minority individual><Modern Man><Molecular><Muscle><Muscle Tissue><NHLBI><NIDDK><NIDDM><National Heart, Lung, and Blood Institute><National Institute of Diabetes and Digestive and Kidney Diseases><Non-Coding><Non-Coding RNA><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-translated RNA><Noncoding RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nontranslated RNA><Novolin R><Obesity><Odds Ratio><Pathway interactions><Pb element><People at risk><Peptides><Persons at risk><Physiologic><Physiological><Physiology><Population><Populations at Risk><Position><Positioning Attribute><Proteins><Proteomics><RNA Seq><RNA sequencing><RNAseq><Race><Races><Regular Insulin><Relative Odds><Risk><Risk Ratio><Risk-associated variant><SEQ-AN><Samoan><Sequence Analyses><Sequence Analysis><Series><Single Base Polymorphism><Single Nucleotide Polymorphism><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><System><T2 DM><T2D><T2DM><TOPMed><Testing><Tissue atlas><Tissues><Trans-Omics for Precision Medicine><Transcript><Translations><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Untranslated RNA><Variant><Variation><Whole Blood><active followup><adiposity><adult onset diabetes><ages><allele variant><allelic frequency><allelic variant><aptamer><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><bio-markers><biobank><biologic><biologic marker><biomarker><biorepository><cardiometabolic><cardiometabolism><case control><case-controlled><catalyst><causation><chromatin immunoprecipitation-sequencing><cohort><corpulence><data portal><data sharing portal><database of Genotypes and Phenotypes><dbGaP><developmental><diabetes><disease causation><entire genome><epigenome><epigenomics><fasting glucose><follow up><follow-up><followed up><followup><full genome><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><glycemic control><heavy metal Pb><heavy metal lead><hemoglobin A1c><hepatic body system><hepatic organ system><high dimensional data><high dimensionality><in silico><insight><insulin resistant><insulin tolerance><islet><ketosis resistant diabetes><liquid chromatography mass spectroscopy><maturity onset diabetes><metabolism measurement><metabolomics><metabonomics><methylomics><multidimensional data><multidimensional datasets><multidisciplinary><muscular><network models><new approaches><noncoding><novel><novel approaches><novel strategies><novel strategy><obesity genetics><pathway><phenomics><polygenic risk score><racial><racial background><racial origin><rare allele><rare mutation><rare variant><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><single nucleotide variant><statistics><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><trait><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translation><type 2 DM><type II DM><type two diabetes><whole genome><whole genome association analysis><whole genome association studies><whole genome association study><work group><working group><β-cell><β-cells><βCell>