Wednesday, January 15, 2025 1/15/2025

Dissecting the effects of genomic variants on neurobehavioral dimensions in CNVs enriched for neuropsychiatric disorders

Award Number: U01MH119759
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The International Consortium on Brain and Behavior Copy Number Variants (IBBC-CNVs) is a collaborative effort of 9 institutions with complementary experience and expertise in phenomics and genomics. The 22q11.2 and 16p11.2 loci are associated with significant risk for neuropsychiatric disorders across the lifespan. The clinical presentations are heterogeneous, manifesting in a range of developmental neuropsychiatric disorders, including Attention Deficit Hyperactivity, Anxiety, Autism Spectrum, and Psychosis Spectrum Disorders. Taking a ‘genetics first’ approach of ascertaining patients based on known, homogeneous genetic etiologies will allow us to overcome barriers posed by the genetic and phenotypic complexity of idiopathic developmental neuropsychiatric disorders. We postulate that CNVs exert a large main effect on psychopathology, but the nature and degree of psychopathology observed in CNV carriers is multifactorial, with contributions from additional rare and common genetic variants, as well as environmental factors. Therefore, dissecting the effects of major CNV hits as well as additional rare and common variants on dimensional measures of psychopathology can elucidate the combined contribution of genetic mechanisms to psychiatric conditions and build models of risk prediction. Notably, the presentation and course of psychopathology in the CNVs resemble these features in idiopathic disorders. Therefore, beyond the specific genetic syndromes investigated, such a cross-CNV effort will identify convergent risk mechanisms for developmental neuropsychiatric disorders that are of relevance to the broader population. We propose to dissect dimensional measures of psychosis, social-emotional processing and neurocognition, and their genetic and environmental modifiers, to elucidate the architecture of risk for neuropsychiatric disorders in CNV carriers. Prospective evaluation with dimensional measures relevant to neuropsychiatric disorders will be applied to a cohort of 2000 individuals with 22q11.2 and 16p11.2 deletions and duplications (500 per group) and their relatives as feasible. In addition, categorical psychiatric diagnoses will be assessed in CNV carriers. Recruitment for prospective phenotyping will leverage existing large cohorts that carry these reciprocal CNVs, many of whom have already been ascertained and characterized with a range of phenotypic measures. New whole genome sequencing (WGS) will be performed in CNV carriers that have not yet been sequenced. We will also utilize existing genetic data from the largest available case-control samples diagnosed with SZ, ASD, and ADHD in the PGC to generate polygenic risk scores. Finally, we will examine family and environmental factors that contribute to the heterogeneity of presentation and developmental course in CNV carriers. This project will establish common phenomic and genomic resources. Our ability to conceive such a large-scale study capitalizes on our existing successful collaborations, complementary expertise, and institutional commitments to achieve these goals.


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 = $0 )
2024	2023	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN				BEL	Mental Health Research Grants	000	5	3/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $102,181 )
2023	2023	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN			BEL	Mental Health Research Grants	001	5	6/1/2023	NON-COMPETING CONTINUATION	$102,181
2023	2022	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN			BEL	Mental Health Research Grants	000	4	1/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $102,181

Issue Date FY: 2022 ( Subtotal = $99,436 )
2022	2022	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN			BEL	Mental Health Research Grants	000	4	3/24/2022	NON-COMPETING CONTINUATION	$99,436
														Subtotal = $99,436

Issue Date FY: 2021 ( Subtotal = $101,866 )
2021	2021	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN			BEL	Mental Health Research Grants	001	3	8/10/2021	NON-COMPETING CONTINUATION	$0
2021	2021	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN			BEL	Mental Health Research Grants	002	3	8/11/2021	NON-COMPETING CONTINUATION	$0
2021	2021	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN			BEL	Mental Health Research Grants	000	3	4/6/2021	NON-COMPETING CONTINUATION	$101,866
														Subtotal = $101,866

Issue Date FY: 2020 ( Subtotal = $104,296 )
2020	2020	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN	3000		BEL	Mental Health Research Grants	000	2	4/2/2020	NON-COMPETING CONTINUATION	$104,296
														Subtotal = $104,296

Issue Date FY: 2019 ( Subtotal = $105,001 )
2019	2019	KATHOLIEKE UNIVERSITEIT TE LEUVEN	OUDE MARKT 13	LEUVEN	LEUVEN	3000		BEL	Mental Health Research Grants	000	1	6/20/2019	NEW	$105,001
														Subtotal = $105,001

Grand Total All Awards = $512,780

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Dissecting the effects of genomic variants on neurobehavioral dimensions in CNVs enriched for neuropsychiatric disorders

Award Number: U01MH119759

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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