# Large-Scale Evaluation of the Effect of Rare Genetic Variants on Psychiatric Symptoms and Cognitive Ability

> **NIH NIH U01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $991,442

## Abstract

PROJECT SUMMARY/ABSTRACT
Rare copy number variants (CNVs) are strongly associated with neuropsychiatric disorders, suggesting that
they might serve as a magnifying glass to study general mechanisms of psychopathology as otherwise subtle
perturbations to neuropsychiatric functions may be more clearly discerned through the major `hit' of the CNV.
However, our understanding of the impact of CNVs on psychiatric symptomatology, RDoC domains and
neurocognitive ability (termed `dimensional neuropsychiatric phenotypes') is limited in at least three ways. First,
the effects sizes of the vast majority of CNVs on neuropsychiatric phenotypes remain poorly understood and
their rarity will likely to prevent individual association studies. Prior studies concentrated on the most recurrent
CNVs, leaving more than 90% of these variants undocumented. Second, for CNVs frequent enough to be
studied individually, the full spectrum of phenotypic variation is unknown because ascertainment has been
performed through neurodevelopmental and specialty clinics, which presumably represent the severe end of
the phenotypic spectrum. Only a few studies have been conducted in unselected populations. Finally, many
CNVs seem to impact the same neuropsychiatric domains, suggesting a poly/omnigenic model for psychiatric
symptomatology, RDoC domains and neurocognitive ability. Based on this hypothesis, our previous work has
shown that genetic scores and functional annotations can accurately predict the effect of any CNV on IQ but
these approaches have not yet been extended beyond IQ to other dimensional neuropsychiatric phenotypes.
We will fill these knowledge gaps with a novel, multidisciplinary, collaborative project that leverages existing
archival data (n=255,303) to estimate and predict the effect sizes of CNVs (duplications and deletions) on
dimensional neuropsychiatric phenotypes. Our aims include 1) phenotypic harmonization; 2) characterizing
previously identified risk CNVs for mental illness in a large in general population cohorts and in samples
ascertained for mental illnesses; 3) examine the contribution of common variants to variable expressivity of
rare CNVs via polygenic risk scores (PRS) in the domains of mood, psychosis, developmental disability, and
general cognitive ability; and 4) develop novel models to explain the effect size of any rare CNVs on
dimensional neuropsychiatric phenotypes. Finally, we will develop tools for data sharing.
Dr. David Glahn, Boston Children's Hospital, Dr. Laura Almasy, Children's Hospital of Philadelphia, and Dr.
Sébastien Jacquemont, Centre Hospitalier Universitaire Sainte-Justine, are co-principal investigators on this
application and bring complementary domains of expertise to the project. As this project involves analysis of
existing archival data, it is an exceptionally cost-effective approach to better characterizing the rare genetic
variants and elucidating general principles regarding the genetic architecture of dimensional neur...

## Key facts

- **NIH application ID:** 9926318
- **Project number:** 5U01MH119690-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Laura A. Almasy
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $991,442
- **Award type:** 5
- **Project period:** 2019-05-06 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926318

## Citation

> US National Institutes of Health, RePORTER application 9926318, Large-Scale Evaluation of the Effect of Rare Genetic Variants on Psychiatric Symptoms and Cognitive Ability (5U01MH119690-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9926318. Licensed CC0.

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