Nine in ten cases have no family history, and for a long time that ninety percent was the part genetics could say least about. It took 13,225 people to find one new position.
Amyotrophic lateral sclerosis destroys the motor neurons — the cells that carry the instruction to move from the brain to the muscles. The muscles are not damaged; the wiring is. Weakness spreads, speech and swallowing fail, and eventually breathing does. It is rapidly progressive and it is fatal.
About one case in ten runs in a family, and those cases have given up their genes relatively readily — SOD1, C9orf72, TARDBP, FUS. The other nine in ten are sporadic, and they were much harder.
A 2014 meta-analysis assembled 13,225 individuals — 6,100 cases and 7,125 controls — from Italy, the Netherlands, the USA, the UK, Sweden, Belgium, France and Ireland, and tested almost 7 million positions. It was the largest association study in ALS at the time.
It found one new locus at genome-wide significance: rs34517613 at 17q11.2, P = 1.11 × 10⁻⁸, odds ratio 0.82. The finding held when combined with a replication cohort.
Before this, the sporadic form had essentially one replicated locus — 9p21.2, the region containing C9orf72.
Compare it with the numbers on our other pages. Schizophrenia: about 8,300 contributing positions. Inflammatory bowel disease: 163 loci. A sample of 13,225 in either of those returns a great deal.
Here it returned one. Sporadic ALS does not look like a common-variant disease with a long tail of small effects. The evidence points instead towards rare variants of larger effect, individually too uncommon for this method to see — which is why the field moved towards sequencing rather than towards larger genotyping arrays.
A study that finds almost nothing, at this size, is telling you something real about where to look next.
It cannot predict ALS, and there is no screening test. There is no preventive treatment, and the available disease-modifying therapy is modest.
If ALS runs in your family, the relevant conversation is with a neurologist and a clinical geneticist about the known familial genes — a sequencing question, answered in a clinic, with counselling around it. It is not a question a consumer genotype file answers, and a variant like the one on this page has nothing to say about it either way.
Source. Fogh et al. (Hum Mol Genet 2014) reported a genome-wide association meta-analysis combining 3,959 newly genotyped Italian individuals (1,982 cases and 1,977 controls) collected by SLAGEN with samples from the Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN — 13,225 individuals in total, 6,100 cases and 7,125 controls, analysed at almost 7 million SNPs. A novel locus reached genome-wide significance at 17q11.2 (rs34517613, P = 1.11 × 10⁻⁸, OR 0.82) and was validated when combined with genotype data from a replication cohort. The authors note that GWAS of the sporadic form — roughly 90% of cases — had previously been unrewarding with the exception of the replicated locus at 9p21.2.
Position listed here. rs34517613 at 17q11.2.
Interpretation. A single genome-wide significant novel locus from 13,225 individuals constrains the genetic architecture: it is not consistent with a large number of common variants of small effect, and it is consistent with a substantial contribution from rarer variants of larger effect that this design has little power to detect. Sequencing-based approaches followed for that reason.
Familial disease is a separate question. Pathogenic variants in C9orf72, SOD1, TARDBP and FUS among others cause familial ALS and are identified by clinical sequencing with genetic counselling, not by common-variant genotyping. Diagnosis of ALS itself is clinical and electrophysiological, with investigations directed at excluding mimics.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Amyotrophic Lateral Sclerosis comes down to these specific, well-studied positions — not a diagnosis.
Because that is what the genetic architecture appears to be. Genome-wide association studies are built to find common variants of small effect, and sporadic ALS does not seem to be made of many of those. The near-empty result from 13,225 people is evidence about where the risk actually lives, and the field moved to sequencing because of it.
No, and it is important to say so plainly. Familial ALS is caused by pathogenic variants in genes such as C9orf72, SOD1, TARDBP and FUS, found by clinical sequencing with genetic counselling around it. That is a different test, a different conversation, and the right one — a neurologist or clinical geneticist rather than a consumer file.
No. An odds ratio of 0.82 against a disease affecting a few people per 100,000 per year carries no useful individual information, and there is no screening test and no preventive treatment for it to lead to.
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