# Human Genetics and Clinical Translation

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $339,822

## Abstract

Project Summary
Adolescent idiopathic scoliosis (AIS) is a twisting condition of the spine and is the most common pediatric
musculoskeletal disorder, affecting 3% of children worldwide. Children with AIS risk severe disfigurement, back
pain, and pulmonary dysfunction later in life. Girls requiring treatment for AIS outnumber boys by more than
five-fold. AIS is treated symptomatically rather than preventively because the underlying etiology is unknown.
Hospital charges for AIS surpass one billion dollars annually in the U.S. and are rising significantly faster than
for other pediatric procedures. Our overall purpose is to understand the biologic causes of AIS as a means to
early diagnosis, prevention and non-invasive biologic treatment. AIS is a complex genetic disease. Genome
wide association studies (GWAS) by our group and others have identified AIS-associated regions harboring
presumed regulatory sequences. For example, with our Project 3 (Genomics) collaborators we have recently
shown that AIS-associated variants disrupt a putative enhancer of the PAX1 gene that is known to participate
in spinal development. We also demonstrated that this locus is specifically associated with AIS in females.
While these GWAS has yielded loci worthy of further study, they cumulatively account for <5% of the total
genetic risk in AIS. In this Project we propose new approaches to identify the genes and mutations expected to
convey substantial disease risk. In one approach we will perform exome-focused GWAS in our collection of
2,750 AIS cases and >20,000 population controls to discover disease-associated mutations in AIS candidate
genes and their regulatory elements. In our second approach we will perform whole genome sequencing
(WGS) in trios with affected males to discover mutations expected to convey strong disease risk. Selected
genes and regulatory sequences will be characterized further by genome editing in zebrafish (Project 2) and
enhancer studies (Project 3). We will define the mutational burden in AIS by large-scale re-sequencing of
candidate genes and regulatory regions discovered in this project by GWAS, as well as those discovered by in
Projects 2 and 3. For example, our Project 2 (Zebrafish) collaborators have discovered that multiple alleles of
kif6 produce an AIS phenotype in zebrafish, prompting us to add this gene to our candidate list. For our
mutation screens we will re-sequence at least 4,000 AIS cases and controls using our established method of
molecular inversion probe-based targeting and massively parallel sequencing. To provide critical reagents for
hypothesis-driven functional analysis of AIS, we will simultaneously expand our existing biobank of DNA, cells,
tissues, and surgical samples from patients ascertained in pediatric orthopaedic centers. Finally, for patients
with defined AIS-causing mutations, we will team with clinical experts in AIS to evaluate potential phenotypic
correlations that may define clinical subtypes. By synergizi...

## Key facts

- **NIH application ID:** 9974359
- **Project number:** 5P01HD084387-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** CAROL A WISE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,822
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974359

## Citation

> US National Institutes of Health, RePORTER application 9974359, Human Genetics and Clinical Translation (5P01HD084387-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9974359. Licensed CC0.

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