Amyotrophic Lateral Sclerosis (ALS) is a rare and deadly neurological disorder affecting voluntary muscle movement. It typically claims victims’ lives about three years after symptoms begin. In the United States,  the condition is more commonly known as Lou Gehrig’s disease, after the Yankees slugger who died of ALS in 1941. About 20,000 people in the U.S. have ALS and one in 100,000 people develop the disease per year.

Despite years of research, relatively little is known about the causes and risk factors of ALS. This week, understanding of the disease moved a step forward with a study published in PNAS that identified several new genetic variants associated with ALS risk.

A team of scientists led by Francois Gros-Louis and Jean-Pierre Julien of Université Laval in Canada analyzed genetic variants in the CHGB gene in more than 700 French and Swedish people with ALS and 750 people without the disease. Although most of the variants found in the CHGB gene were rare, one of the more common variants was markedly more frequent in those with ALS than in those without. The rarer T version of this SNP, rs742710, was associated with about 2.4 times increased odds of ALS, compared to the more prevalent C version. The SNP also seemed to affect age-of-onset: individuals with the T version of rs742710 tended to develop ALS about 10 years earlier than individuals with two copies of the C version.

(23andMe Complete Edition customers can check their data for rs742710 using the Browse Raw Data feature.)

One of the hallmarks of ALS and some other neurodegenerative diseases is the abnormal aggregation of proteins within cells. Many of these aggregations appear in organelles known as the endoplasmic reticulum (ER) and the Golgi network, which are tasked with processing proteins into their mature forms and readying certain ones to be secreted, or released outside the cell.

Gros-Louis and his team focused on the CHGB gene because of its “guilt-by-association” relationship with SOD1, one of the few established genetic factors linked to ALS. Abnormal SOD1 proteins tend to aggregate in motor neurons of people with ALS, and recent reports have found chromogranin B, the protein encoded by CHGB, near these aggregates.

Chromogranin B is typically secreted from cells like a hormone, and so the researchers hypothesized that genetic variants in CHGB associated with increased risk for ALS might impair secretion of chromogranin B. Sure enough, in cells with CHGB containing the T version of rs742710, almost all of the protein remained sequestered inside the ER/Golgi network.  In cells with normal CHGB, only 40% of the chromogranin B protein was found there.

Previous studies in this area have indicated that stress and damage to the ER and Golgi are a defining characteristic of ALS-affected motor neurons. Gros-Louis and his colleagues suggest that further research be done to investigate whether CHGB variants like rs742710 stress the ER-Golgi system and hasten the deterioration of motor neurons.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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No one understands how or why millions of Americans are afflicted with restless legs syndrome, a “creepy-crawly” sensation that compels them to move their legs while lying in bed at night. The phenomenon is so strange and poorly understood, in fact, that some physicians even question whether the seriousness and extent of restless legs syndrome has been over-hyped.

A report published today in Nature Genetics could change some minds about the mysterious condition. New research shows that two SNPs, both located in a gene that encodes a brain signaling protein, may influence who is affected by restless legs syndrome (RLS).

A study of 2,458 sufferers and 4,749 people without the condition from Germany, Austria, The Czech Republic and Canada has shown that versions of both rs1975197 and rs4626664 increase the risk of having RLS.

23andMe customers can check their data for rs1975197 using our Browse Raw Data feature. According to the study, compared to the much more common GG genotype, each A at rs1975197 increases the odds of RLS by 1.31. The riskier version of rs4626664 had a similar effect, with each copy increasing the odds of having RLS by 1.44 times. (23andMe does not report data for this SNP at this time)

RLS has been recognized in the medical literature since 1683, but didn’t gain its official name until 1945. The involvement of genes in the disorder has been suspected since the 1920s. Studies of affected families have identified broad regions of the genome that could contain genes influencing RLS, and recently scientists have been narrowing in on various candidates using genome-wide association studies of SNPs.

In 2007 the same research group behind the new study by Schormair et al published results describing three other RLS-associated SNPs. One of these SNPs (rs3923809 in BTBD9) was replicated by a separate group and is described in detail in the 23andMe My Gene Journal (now called Health and Traits) article on Restless Legs Syndrome.

The newly identified SNPs, rs1975197 and rs4626664, are located in PTPRD, a gene that encodes a signaling protein expressed in the brain. Mouse studies have shown that this protein is important for motor neuron development. These nerve cells connect the central nervous system to the musculature, making their involvement in RLS an attractive theory.

RLS cannot be definitively diagnosed with a blood test or other measure. Instead, patients are classified as having the disorder if the symptoms they describe fit with several criteria. Some have argued that “disease mongering” on the part of drug companies and the media has convinced healthy people that they have RLS and should seek treatment. As more genetic associations like those reported today are found for RLS, the underlying biology of the disorder may become more clear, allowing more definitive diagnoses.

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