19 Dec 2007

Working independently, two European-led research groups may have uncovered an important clue to the mystery of amyotrophic lateral sclerosis (ALS), better known to some as Lou Gehrig or motor neuron disease. Both groups used genomewide association studies to identify genetic variations that increase the risk for developing this fatal neurodegenerative disorder. Both groups also arrived at the same conclusion: the strongest genetic link to ALS is a single nucleotide polymorphism (SNP) in a gene called DPP6 (or DPPX), which codes for a protein that appears to be an integral part of type A potassium channels. The finding may provide a new lead in understanding the causes of ALS.

The first group, led by Simon Cronin at Beaumont Hospital, Dublin, Ireland, carried out a genomewide association study of 222 Irish patients with sporadic ALS and 217 controls. Their findings appear in the December 15 Human Molecular Genetics online. The researchers genotyped DNA samples using an Illumina DNA chip, which is capable of identifying more than 550,000 SNPs at a time. They found 35 SNPs that associated with ALS with a p value of less than 1x10^-4. However, none of them reached the Bonferroni statistical threshold of significance of p -7, and the authors therefore conclude that “discussion of the biological significance of the 35 SNPs that were most associated with ALS in the Irish cohort would be premature.” Instead, they aimed for validation by comparing their findings with recently published U.S. (Schymick et al., 2007) and Dutch data (van Es, 2007). Running a combined analysis, they identified the DPP variation (rs10260404) as the top-ranking SNP, being associated with ALS in all three datasets.

Researchers led by Leonard van den Berg at University Medical Center Utrecht, the Netherlands, adopted a similar approach to garner enough statistical power to meet the Bonferroni criteria. Writing in the December 16 Nature Genetics online, first author Michael van Es and colleagues report that combining their earlier data with the U.S data (again Schymick et al., 2007) identified 15 SNPs that were then further analyzed on additional independent populations from the Netherlands (272 cases, 336 controls), Sweden (467 cases, 437 controls), and Belgium (291 cases, 420 controls). The combined analysis showed that the DPP SNP was the strongest link, and with a p value of 0.5 x 10^-7, the association was statistically significant. Pooled analysis suggests that the DPP6 variant increases risk for ALS by 37 percent.

Called rs10260404, the DPP variant represents the strongest genetic link to sporadic ALS to date. Though ALS risk genes had been identified previously in certain populations, “attempts to replicate these findings in other populations have frequently failed,” write van Es and colleagues. This problem has beset AD genetics, as well. The DPP SNP turned up in Irish, Dutch, U.S., Belgian, and Swedish populations, and therefore inspires more confidence.

A next question is how this DPP SNP confers risk. Is it functionally significant by itself, or does that distinction fall to nearby SNPs that are in linkage disequilibrium, i.e., co-inherited with the DPP SNP? Because the DPP SNP lies in an intron (i.e., gets spliced out before protein translation), at first blush it does not appear a likely candidate. On the other hand, six other SNPs located in a 50 kb block of DNA that the Dutch group found to be inherited with the DPP SNP all reside in the same DPP intron. Furthermore, the researchers were able to rule out SNPs outside the 50 kb region; that is, 130 other variants within a larger 900 kb zone surrounding the DPP LD block were not associated with the disease. “Because the entire associated 50-kb LD block containing rs10260404 is located within intron 3 of DPP6, and there are no known genes or microRNAs nearby, we consider this to be the putative ALS-associated gene,” write the authors.

DPP6 codes for a protein with structural similarities to dipeptidyl aminopeptidases. Even so, it appears to be an integral part of neuronal A-type potassium channels (see Nadal et al., 2003). Since impaired potassium channel function has been found in ALS patients (see, for example, Kanai et al., 2006), DPP6 could be a new link to ALS pathology.—Tom Fagan

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References

Paper Citations

1. Schymick JC, Scholz SW, Fung HC, Britton A, Arepalli S, Gibbs JR, Lombardo F, Matarin M, Kasperaviciute D, Hernandez DG, Crews C, Bruijn L, Rothstein J, Mora G, Restagno G, Chiò A, Singleton A, Hardy J, Traynor BJ. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 2007 Apr;6(4):322-8. PubMed.
2. van Es MA, van Vught PW, Blauw HM, Franke L, Saris CG, Andersen PM, Van Den Bosch L, de Jong SW, van 't Slot R, Birve A, Lemmens R, de Jong V, Baas F, Schelhaas HJ, Sleegers K, Van Broeckhoven C, Wokke JH, Wijmenga C, Robberecht W, Veldink JH, Ophoff RA, van den Berg LH. ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol. 2007 Oct;6(10):869-77. PubMed.
3. Nadal MS, Ozaita A, Amarillo Y, Vega-Saenz de Miera E, Ma Y, Mo W, Goldberg EM, Misumi Y, Ikehara Y, Neubert TA, Rudy B. The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron. 2003 Feb 6;37(3):449-61. PubMed.
4. Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori T, Bostock H. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain. 2006 Apr;129(Pt 4):953-62. Epub 2006 Feb 8 PubMed.

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