# Investigating tandem repeat expansions as a cause of schizophrenia

> **NIH NIH R03** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $84,500

## Abstract

Tandem Repeat Expansions (TREs), most commonly of triplet repeats such as poly(CAG), are known to
underlie >30 different human neurological diseases. While the majority of TREs identified to date have been
found in late-onset neuro-degenerative disorders such as hereditary ataxias and Huntington disease, TREs
have been identified in patients with schizophrenia. In addition to expansions of short tandem repeats (those
with motif sizes between 1 and 6 base pairs), copy number variation of larger repeats with motifs ≥10bp, also
known as Variable Number of Tandem Repeats (VNTRs), has recently been linked to schizophrenia risk.
However, despite this evidence that variation in tandem repeat (TR) sequences can act as the causative
mutations in some cases of schizophrenia, there have been no concerted efforts in schizophrenia cohorts to
either systematically screen for novel TREs, or to genotype VNTR copy numbers.
 Newly developed bioinformatic approaches that can be applied to analyze Whole Exome Sequencing
(WES) data now provide an opportunity to fill this knowledge gap. Utilizing the expertise and knowledge that
we have gained working on other large datasets, we propose to apply these approaches to analyze >20,000
exomes that are available to the community, and will use these data to investigate two hypotheses:
 1. We hypothesize that some cases of schizophrenia are caused by rare, highly penetrant pathogenic
 TREs. Using novel bioinformatic tools that can identify TREs, we will search for rare TREs that (i) using a
 trio design, occur as de novo mutations in schizophrenia cases, or (ii) using a case:control design, occur
 uniquely in or show significant enrichment in schizophrenia cases compared to controls, and thus are
 likely causative for schizophrenia.
 2. We hypothesize that common polymorphic copy number variation of VNTRs can act as genetic risk
 factors for schizophrenia. We have developed a novel approach based on read depth to estimate copy
 number of VNTRs from exome sequencing data. We will analyze available WES data from 6,135
 unrelated schizophrenia cases and 6,245 ethnically matched controls, generating copy number estimates
 for ~4,100 genic VNTRs that are represented in WES, which will be used to perform association analysis
 of VNTR copy number with schizophrenia status in a case:control study.
Given that TREs, and polymorphic variation in VNTRs, both represent established mutational mechanisms that
contribute to a variety of late-onset neuro-degenerative conditions, we believe that the study of TR variation in
schizophrenia represents a logical step that has a high likelihood of uncovering novel genetic causes of
schizophrenia.

## Key facts

- **NIH application ID:** 10426348
- **Project number:** 5R03MH126147-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Andrew James Sharp
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $84,500
- **Award type:** 5
- **Project period:** 2021-06-10 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426348

## Citation

> US National Institutes of Health, RePORTER application 10426348, Investigating tandem repeat expansions as a cause of schizophrenia (5R03MH126147-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10426348. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*