Large Genetic Analysis Newly Links 5 Genes to Sporadic ALS

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by Steve Bryson PhD |

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ALS and genes

A combined analysis using people of Japanese, Chinese, and European ancestry identified five new genes associated with the non-familial, sporadic form of amyotrophic lateral sclerosis (ALS). 

These findings further an understanding of the genetic basis of sporadic ALS, and may support the development of new therapies.

The study, “A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis,” was published in the journal Nature Communications Biology. 

Familial ALS is very rare, with only about 5% to 10% of ALS cases being linked to inherited genes.  Most ALS cases are sporadic, or not linked to close family members; still, underlying genetic variations are thought to influence susceptibility to ALS without directly causing it.

In support of a genetic component to sporadic ALS, a study of twins (where at least one twin had non-inherited disease) found some identical twins were affected, and no non-identical twins were.

To further investigate genetics and sporadic ALS, researchers at Nagoya University Graduate School of Medicine in Japan conducted a genome-wide associated study (GWAS) to find links between genes and ALS in a Japanese population.

In GWAS studies, the entire genome from many different people is scanned to identify specific genetic variations that are associated with particular diseases. DNA was analyzed from blood samples collected from 1,173 sporadic ALS patients who were part of the Japanese Consortium for ALS research. Samples from 8,925 people without ALS were included as controls.

This investigation did not find genes associated with sporadic ALS. To strengthen their analysis, researchers then combined this Japanese group’s findings with those of patients from a similar large-scale study of  people with European ancestry. This study included 20,806 ALS patients and 53,439 controls. 

An analysis now uncovered four genes previously associated with ALS: GPX3-TNIP1, C9orf72, TBK1, and UNC13A

Researchers also found three single nucleotide polymorphisms (SNPs) — rs58854276, rs11195948, and rs3736947 — in a previously unidentified gene called ACSL5. (SNPs are single changes to the genetic code within a gene that can be linked to specific conditions.) 

The ACSL5 gene provides the instructions for a protein that plays an essential role in fat (lipid) metabolism. Its production is elevated in brain cells called A1 astrocytes, which are abundant in various neurodegenerative diseases, including ALS, as they induce the death of nerve cells (neurons). 

To validate these results, the team analyzed two combined datasets covering 1,234 ALS cases and 2,850 controls, all involving people of Chinese descent, and an independent new Japanese dataset covering 707 ALS cases and 971 controls. Two of the three SNPs in ACSL5 — rs11195948 and rs3736947 — were validated, with rs11195948 being showing the most statistically significant link. 

A further analysis that combined the Japanese, European, and Chinese populations — covering 23,213 patients and 71,579 controls — also associated the same three SNPs with sporadic ALS.

A functional test revealed a significant relationship between the rs3736947 risk SNP and ACSL5 expression, in which the risk SNP was linked to greater ACSL5 gene activity. 

The investigators suggested that “increased expression of ACSL5 could induce A1 astrocytes, cause motor neuron death, and lead to ALS development.”

A gene-based association analysis using all three populations again confirmed already discovered genes associated with ALS: TNIP1, C9orf72, KIF5A, and SCFD1Along with ACSL5, four new genes reached significance: ERGIC1, RAPGEF5, FNBP1, ATXN3.

The ERGIC1 gene encodes for a protein located in the cellular compartment known as the endoplasmic reticulum (ER) and the Golgi. Problems with ER–Golgi transport are reported to be a common mechanism in familial ALS.

The RAPGEF5 gene carries instructions for a protein produced mostly in the brain, and associated with neuronal growth. The FNBP1 gene codes for a cell membrane protein; it is produced in excess in the spinal cord of an ALS mouse model.

Finally, the ATXN3 gene encodes a protein linked to a condition called spinocerebellar ataxia type 3, which shares common pathologies with familial ALS, such as TDP-43 protein clumps in motor nerve cells.

“In conclusion, multi-ethnic GWAS identified the association of the ACSL5 [gene] with ALS,” the investigators wrote. “In addition, gene-based analysis identified ERGIC1, RAPGEF5, FNBP1, ACSL5, and ATXN3.”

“While these genes reached the discovery stage of the analysis, further replication analysis or functional analysis in ALS is warranted,” they added.