In an ALS Association-funded study conducted in Finland, researchers found that a major cause of familial ALS was located on chromosome 9p21. Finland is a well suited location for a genome-wide association (GWA) study of ALS because the incidence of the ALS is one of the highest in the world, and the genetic background of the Finnish population is relatively homogenous. Previous GWA studies have failed to identify a single location that is significant and can be replicated in other studies probably because of the heterogeneity of the disease.
“Although GWA study has been a disappointing approach to find new genes linked to sporadic ALS, it is encouraging to see the approach used successfully in a more homogeneous population,” said ALS Association Chief Scientist Dr. Lucie Bruijn, Ph.D.
In the study published in Lancet Neurology, 853 DNA samples were collected from 442 people with ALS and 521 control individuals. Control samples were from a population-based study of elderly Finnish individuals. People known to carry the SOD1 gene were included in the final analysis as positive controls to assess whether this genome-wide association study was able to detect an association signal.
Two signal peaks were identified in the population that reached significance: one peak corresponding to the known autosomal recessive D90A mutation of the SOD1 gene and the second corresponding to chromosome 9p21.2 a location previously linked to autosomal dominant ALS, where the gene is passed from just one parent.
The study therefore describes a major cause of familial ALS in the Finland located on chromosome 9p21. Furthermore, the overlap with the risk haplotype (a combination of DNA sequences) recently also reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. Although the investigators are currently unable to identify the specific genetic variation underlying this locus, it will be feasible to identify patients with chromosome 9p21-linked ALS by sequencing for this risk haplotype.
The research team was led by Bryan Traynor, a neurogeneticist with the National Institute on Aging and with the Johns Hopkins School of Medicine. "We are very excited about this result because for the first time, we have been able to explain a large proportion of ALS cases in a population, Taynor said. “We will continue to pursue this chromosome 9 locus to understand how it gives rise to disease.”
In addition to The ALS Association, funding for this project came from National Institutes of Health and National Institute on Aging, Microsoft Research, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.