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Functional and population genetic architectures of complex disease

Award Number: R01MH101244
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Functional and population genetic architectures of complex disease - Project Summary Recent progress in the genetics of complex diseases, including neuropsychiatric diseases, has revealed that the bulk of disease heritability is explained by the action of many common non-coding variants. Most of these variants exert individually tiny effects on disease risk, but collectively they contribute most of the measurable genetic risk for most diseases and typically account for between a third and half of twin estimates of heritability. These observations motivate three important questions concerning the biology underlying phenotypic variation: First, how do individual non-coding variants associated to disease impact biological function? A growing number of studies, including those published by the Key Personnel of this renewal application, provide statistical analyses that link genetic and epigenetic data to identify regulatory elements active in cell types that are key to disease biology. However, the mechanism of regulatory action is understood just for a few examples of genetic associations to disease. Second, how do the causative variants conspire together to perturb genes, biological pathways and networks and induce a disease phenotype? Despite the body of knowledge on genes and functional modules accumulated by decades of experimental research, we lack understanding of specific gene programs and networks through which the thousands of causative variants act to impact disease phenotypes. Third, how is genetic variation associated to common neuropsychiatric diseases stably maintained in the population given the loss of fitness associated to these disorders? Established population genetics models applicable to rare diseases are inconsistent with recent data on common disease genetics. We propose to develop new statistical and computational methods to generate biological insights from genomic data and to apply these methods to genome-scale genotype-phenotype datasets. We will design new strategies to combine functional genomic and molecular phenotype data with disease association results to shed light on the proximal regulatory function of non-coding variants. We propose new statistical methods to interpret genetic association data at different levels of biological organization ranging from individual regulatory interactions to genes, pathways and networks. We will use population genetics models to address conceptual issues of the origin of allelic architecture of common disease and, in particular, neuropsychiatric diseases. Our collaboration has an extensive publication record and a record of producing widely-used open-source software in the previous funding cycle. We have extensive computational and statistical expertise, but our approach is always rooted in data. All proposed method development will be guided by available large-scale genetics datasets and functional genomics datasets spanning over 2 million samples.


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: 2024 ( Subtotal = $788,253 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	13	6/13/2024	NON-COMPETING CONTINUATION	$788,253
2024	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	11	5/15/2024	COMPETING CONTINUATION	$278,547
2024	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	10	5/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$278,547
														Subtotal = $788,253

Issue Date FY: 2023 ( Subtotal = $804,835 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	003	12	7/1/2023	NON-COMPETING CONTINUATION	$804,835
2023	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	11	3/30/2023	COMPETING CONTINUATION	$0
2023	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	10	10/24/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$223,090
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	9	10/24/2022	NON-COMPETING CONTINUATION	-$223,090
														Subtotal = $804,835

Issue Date FY: 2022 ( Subtotal = $893,341 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	11	8/2/2022	COMPETING CONTINUATION	$839,908
2022	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	10	7/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$496,215
2022	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	9	7/28/2022	NON-COMPETING CONTINUATION	-$442,782
														Subtotal = $893,341

Issue Date FY: 2021 ( Subtotal = $686,231 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	9	7/2/2021	NON-COMPETING CONTINUATION	$686,231
														Subtotal = $686,231

Issue Date FY: 2020 ( Subtotal = $690,534 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	8	6/29/2020	NON-COMPETING CONTINUATION	$690,534
														Subtotal = $690,534

Issue Date FY: 2019 ( Subtotal = $691,264 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	7	7/25/2019	NON-COMPETING CONTINUATION	$691,264
2019	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	6	6/7/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $691,264

Issue Date FY: 2018 ( Subtotal = $700,491 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	6	8/29/2018	NON-COMPETING CONTINUATION	$700,491
2018	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	4	10/23/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $700,491

Issue Date FY: 2017 ( Subtotal = $775,877 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	5	9/12/2017	COMPETING CONTINUATION	$775,877
2017	2015	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	3	12/12/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $775,877

Issue Date FY: 2016 ( Subtotal = $451,985 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	4	8/5/2016	EXTENSION WITH OR WITHOUT FUNDS	$451,985
														Subtotal = $451,985

Issue Date FY: 2015 ( Subtotal = $451,985 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	3	7/27/2015	NON-COMPETING CONTINUATION	$451,985
														Subtotal = $451,985

Issue Date FY: 2014 ( Subtotal = $451,871 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	8/5/2014	NON-COMPETING CONTINUATION	$451,871
														Subtotal = $451,871

Issue Date FY: 2013 ( Subtotal = $539,763 )
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	8/9/2013	NEW	$539,763
														Subtotal = $539,763

Grand Total All Awards = $7,926,430

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Functional and population genetic architectures of complex disease

Award Number: R01MH101244

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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