Cross-ethnic Genome Studies Link GPX3-TNIP1 Genes to ALS Development

A new genome wide association study (GWAS) conducted in multi-ethnic patients with amyotrophic lateral sclerosis (ALS) has demonstrated that the GPX3-TNIP1 gene locus is significantly associated with ALS.

The study, “Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis,” was published in Nature Communications.

Approximately 10% of ALS patients inherit ALS-inducing mutations, and the prevalence of these mutations differs across families and backgrounds. The remaining 90% of patients develop sporadic ALS.

SOD1, C9orf72, TARDBP, FUS, and TBK are just some of the genetic mutations that have been associated with the disease.

Researchers estimate that single-nucleotide polymorphisms (SNPs), a type of mutation affecting only one nucleotide in a gene sequence, accounts for about 8.5% of ALS cases that have a genetic component. But to date, only 0.2% of these SNPs have been identified, including C9orf72, UNC13A, SARM1, MOBP, SCFD1, and C21orf2.

Researchers hypothesize that increasing the sample size of patients will help identify more SNPs associated with ALS.

The lifetime risk of ALS, the peak age of onset, and the survival of patients differs across ethnicities. Currently, most studies that map genetic variants to ALS have been conducted in European populations.

However, expanding studies to other ethnicities may help identify common variants that are most likely ancient and shared between ethnic groups. So researchers conducted a cross-ethnic meta-analysis for European patients and Chinese patients, the results of which were then compared to two independent Australian group studies.

Researchers discovered a new locus, or gene location, that is associated with ALS. The locus is located on chromosome 5 and spans the genes SPX3 and TNIP1. The risk for this variant is higher in the Chinese than the European population, but the result was also found in the two independent Australian populations.

Until now, the GPX3 and TNIP1 genes have not been implicated in the development of ALS.

Gpx3 is an antioxidant molecule that is related to SOD1, which is known to play a role in ALS. In a rat model of ALS, the Gpx3 protein was found to be higher in the pre-symptomatic stage of the ALS rats compared to controls. By the disease end-stage, Gpx3 protein was much lower compared to the controls, which is similar to Gpx3 levels in humans with ALS.

Both Gpx3 and TNIP1 are associated the NF-kB pathway, which helps regulate the inflammatory response. Additionally, when looking at protein-protein interactions, it was found that the TNIP1 protein is linked to OPTN, mutations of which are associated with cases of familial ALS.

“In summary, using a cross-ethnic design, we identify association of the GPX3-TNIP1 locus with ALS. This locus was identified by combining GWAS results from our Chinese data with the largest European GWAS data and replicated in independent Australian samples,” the research team concluded. “The discovery of a novel risk locus significantly advances our understanding of ALS etiology.”