# Integrated analyses of genome sequencing in adolescent idiopathic scoliosis families

> **NIH NIH R03** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $137,747

## Abstract

Project Summary/Abstract
Adolescent Idiopathic scoliosis (AIS) is the most common pediatric spinal deformity and exhibits a remarkable
sexual dimorphism. AIS affects ~3% of children worldwide, and significantly impacts national health in the U.S.,
creating severe disfigurement and disability and costing billions of dollars annually for treatment. AIS is a
genetically complex disease, and the majority of genetic risk alleles have not been defined. Our long-term
objective is to identify genetic underpinnings in AIS that will provide insights into disease pathogenesis in order
to enable pre-symptomatic diagnosis and develop biologic treatments and cures. Our group and other
researchers previously identified and validated common variant associations with AIS by population-based
genome-wide association studies (GWAS). Although GWASs have succeeded in explaining a small fraction of
the genetic components in AIS, recent advances in next-generation sequencing technologies, such as whole
genome sequencing (GS) and whole exome sequencing (ES), would rapidly facilitate discovery of rare single
nucleotide polymorphisms (SNPs) and copy number variations (CNVs) that are expected to contribute
substantially to disease risk. We have partnered with the Gabriella Miller Kids First (GMKF) initiative and
sequenced 591 genomes of multiplex AIS families. The primary purpose of the studies described in this proposal
is to perform an integrated analysis of GS, ES and regulome data to define new, biologically-interpretable genetic
risk factors. Aim 1 is to perform comprehensive risk allele discovery analyses with emphasis on rare, high-risk
variants (SNVs and CNVs) using GS data in 190 AIS families. We will search for rare variants in both protein-
coding and non-coding regulatory elements in our unique AIS family cohort by combined linkage, inheritance
and de novo mapping strategies. This will be further powered by utilizing GS data from 10,746 non-scoliosis
participants in 9 additional GMKF studies to generate a database of at least 1000 genome controls for rare
variant annotation and filtration. Then in Aim 2, we will assess the overlap of AIS candidate genes from Aim 1
with genes identified by burden tests in an independent cohort of 1,320 AIS exomes and 7,500 ancestry-matched
control exomes. Candidates identified in Aim 1 will be compared to these analyses to enable identification of
common genes or pathways. Scoliosis often occurs in children diagnosed with other structural birth defects such
as congenital heart disease. We have noted that 452 probands (excluding our own) in the GMKF portal are listed
as having scoliosis. We will endeavor to work with other GMKF investigators to evaluate candidate genes in
common across diagnoses. These studies will reveal AIS susceptibility loci in genes with strong effects across
patient populations. These findings will form the cornerstone of many future studies ultimately targeting
alternative treatments and preventions.

## Key facts

- **NIH application ID:** 10195530
- **Project number:** 1R03HD105110-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** CAROL A WISE
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $137,747
- **Award type:** 1
- **Project period:** 2021-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195530

## Citation

> US National Institutes of Health, RePORTER application 10195530, Integrated analyses of genome sequencing in adolescent idiopathic scoliosis families (1R03HD105110-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10195530. Licensed CC0.

---

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