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Rare Sequence Variation and Diabetes Quantitative Traits

Award Number: U01DK078616
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2007
PERIOD OF PERFORMANCE END DATE: 12/31/2020

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Rare Sequence Variation and Diabetes Quantitative Traits - ¿ DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a growing scourge worldwide, despite attempts to prevent and control it. Innovative approaches are needed to identify new molecular targets for prevention and care. Genome-wide association studies (GWAS) for T2D and related quantitative traits (QTs: fasting glucose [FG], insulin [FI], glycated hemoglobin [HbA1c]) have dramatically advanced molecular understanding of glycemic regulation, with >120 common (minor allele frequency, MAF =1%) single nucleotide variants (SNV) and ~110 genomic loci now associated with T2D and-or QTs. However, the causal variant and the functional basis of associations are unclear at many loci, and most signals reside in non-coding regions. More detailed scans of rare variants (MAF <1%) and non-coding regions available from whole genome sequence (WGS) are needed to help translate T2D genetics into better T2D healthcare. Rare variation makes up ~2/3 of all human genetic variation. Non-coding regions occupy >98% of the genome. Both rare and common variants are captured in WGS data and can be scanned genome-wide for trait associations, then further tested for association with T2D and other clinical phenotypes using extant data. SNVs can be integrated with detailed regulatory maps (e.g. ENCODE, many others) to define molecular function-trait associations. Genomic annotation can point to specific "disruptive" mutations (altering gene regulation or function, producing phenotype variation) potentially acting at a locus, suggesting specific in vitro assays to confirm the annotation's prediction. The overall goal to renew 2R01DK78616 is to identify T2D-QT- associated functional rare variants using WGS scans in ~3,700 white and black individuals from three cohorts in the CHARGE consortium. We will manage WGS data in the "cloud" and analyze individual data in a "Commons". We will replicate new findings in collaboration with other WGS studies. Our Aims are 1) test WGS-wide for FG and FI rare variant associations at ~110 known and new T2D-QT loci; 2) Phenotype T2D-QT rare variants with existing physiological and molecular data in CHARGE, including tests of QT variant associations with T2D risk; 3) Annotate T2D-QT SNVs using ENCODE and others, and confirm their predicted allele-specific molecular function in vitro with appropriate experiments in appropriate cells (For instance, test allele-specific effects at transcription facto binding sites with transient transfection, gel shift and luciferase assays in HepG2 cell lines). Ou interdisciplinary, multicenter team has a proven track record based on over six years of R01DK78616 support. We now propose to move T2D genetics from common variant GWAS to rare variant WGS with deep annotation and in vitro validation to generate new molecular hypotheses and advance translation of T2D genetics into better T2D prevention and care.


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: 2021 ( Subtotal = -$102 )
2021	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	7/31/2021	NON-COMPETING CONTINUATION	-$102
2021	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	12/14/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = -$102

Issue Date FY: 2019 ( Subtotal = $699,443 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	9/2/2019	NON-COMPETING CONTINUATION	$0
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/26/2019	NON-COMPETING CONTINUATION	$699,443
														Subtotal = $699,443

Issue Date FY: 2018 ( Subtotal = $700,599 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	8/29/2018	NON-COMPETING CONTINUATION	$0
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/13/2018	NON-COMPETING CONTINUATION	$700,599
														Subtotal = $700,599

Issue Date FY: 2017 ( Subtotal = $717,492 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	6/16/2017	NON-COMPETING CONTINUATION	$69,842
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	4/27/2017	NON-COMPETING CONTINUATION	$628,589
2017	2015	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	5/19/2017	COMPETING CONTINUATION	$19,061
														Subtotal = $717,492

Issue Date FY: 2016 ( Subtotal = $702,240 )
2016	2016	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	6/10/2016	NON-COMPETING CONTINUATION	$702,240
2016	2015	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	2/2/2016	COMPETING CONTINUATION	$0
														Subtotal = $702,240

Grand Total All Awards = $2,819,672

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Rare Sequence Variation and Diabetes Quantitative Traits

Award Number: U01DK078616

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/01/2007

PERIOD OF PERFORMANCE END DATE: 12/31/2020

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