ALS GWAS Confirm Chromosome 9 Risk Factor—But What Is It

Two genetic studies described in this week’s Lancet Neurology online point squarely at the p arm of chromosome 9, where lurks an important risk factor for amyotrophic lateral sclerosis (ALS). Unfortunately, simple sequencing failed to yield the responsible mutation. The papers, both posted online August 27, describe genomewide association studies in a Finnish population and in a diverse group, with a study out of the U.K. including all published GWAS data to date. Combined with previous family and GWASs, chromosome 9 is looking quite intriguing—if only researchers could nab the genetic culprit.

Multiple studies have suggested that some genetic risk factor for both ALS and the related frontotemporal dementia (FTD) resides on the short arm of chromosome 9 (see ARF related news story on Gijselinck et al., 2010; ARF related news story on van Es et al., 2009; Morita et al., 2006; Vance et al., 2006; Boxer et al., 2010; Valdmanis et al., 2007). The two current papers provide important confirmation. This is very strong evidence that chromosome 9p is a very important risk factor for ALS, said Rosa Rademakers of the Mayo Clinic in Jacksonville, Florida, who was not involved in the study reported in the Lancet Neurology papers. It is like ApoE in Alzheimer’s, she said.

Pentti Tienari of the University of Helsinki, Finland, and Bryan Traynor of the National Institute on Aging in Bethesda, Maryland, chose to focus their analysis on Finland. That’s because the country’s small founder population and past genetic bottlenecks—i.e., dramatic reductions in the number of people who can reproduce—have made its citizens genetically more homogenous than most, and thus rendered them fertile ground for gene hunters (see the Finnish Disease Heritage website). Finns have a high rate of genetic diseases (reviewed in Kere, 2001), of which ALS is one (Murros and Fogelholm, 1983). In fact, Finland has the highest incidence of ALS outside of the Pacific Rim, where an unusual form of ALS arose in Guam and other isolated locations.

Our GWAS, for the first time in any population, has been able to explain this excess of [ALS] cases, Traynor said.

The researchers, including joint first authors Hannu Laaksovirta and Terhi Peuralinna of the University of Helsinki, and Jennifer Schymick of the NIA, sampled DNA from 405 people with ALS and 497 control cases. They found strong association for single nucleotide polymorphisms (SNPs) near the gene for superoxide dismutase—a well-known ALS gene—as well as the 9p21 locus. Those with the disease-linked SNPs on 9p21 included 44 people with a family history of ALS, as well as 58 whose disease was apparently sporadic.

However, a case that looks sporadic may not necessarily be a new mutation, Traynor noted, and he thinks some of those people may have inherited the gene. They all share a common founder, he suggested. Rademakers added that this unknown risk factor could have incomplete penetrance, which could spare carriers from overt ALS. Sporadic cases may have a parent who was lucky enough not to get sick, or who did not live long enough to show symptoms.

ALS and FTD appear to be opposite ends of a spectrum of a disease with similar causes. Finland has a very high rate of frontotemporal dementia as well, Traynor noted. Probably the cases of frontotemporal dementia are stemming from this chromosome 9.

Scientists in the U.K. took a slightly different tack. The group, led by first author Aleksey Shatunov and senior author Ammar Al-Chalabi of King’s College London, first performed a local study with 599 patients and 4,144 controls. Then, they collected data from all previous GWASs in ALS (van Es et al., 2009; Cronin et al., 2008; Landers et al., 2009; Schymick et al., 2007), for a grand total of 4,312 patients and 8,425 controls. Traynor was also a collaborator on this study. The only locus to reach statistical significance was 9p21. However, the study failed to find significance for other loci that smaller GWASs linked to ALS. The finding of 9p21 in this large, diverse collection of samples suggests it may be the most significant genetic risk factor for ALS, Rademakers said.

The most important finding from this study is that none of the previously associated SNPs in ITPR2, FGGY, DPP6, and UNC13A achieved significance, wrote Guy Rouleau and colleagues from the Universit de Montral in Quebec, in a commentary accompanying the two Lancet Neurology papers. Those previous genes could have been false positives, they suggested (see ARF related news story on Cronin et al., 2008 and van Es et al., 2008; Dunckley et al., 2007; van Es et al., 2007).

If the 9p21 locus is so important in ALS and FTD, then where is the mutation—the actual genetic lesion that would explain all that GWAS and linkage data The answer is so elusive that among scientists studying a family with FTD dubbed VSM-20 (for Vancouver-San Francisco-Mayo Clinic; see Boxer et al., 2010), Bradley Boeve of Mayo’s Rochester, Minnesota, branch has joked the acronym really stands for Very Sneaky Mutation.

The 9p21 region of interest, which Traynor and colleagues narrowed to 232 kilobases, contains three known genes, and none of them exactly screams motor neuron disease. MOBKL2B regulates kinases; IFNK is an interferon precursor involved in immunity to viruses; C9orf72, it is thought, might have a function in cell development or spermatogenesis (Beaver et al., 2010). Traynor and colleagues sequenced the coding regions for all three genes, but found nothing suspicious.

However, there are several kinds of mutations that sequencing might miss. The mutation could fall in an unknown gene or exon, the U.K. authors suggest. It could also be an inversion, which would be hard to catch via sequencing. Rademakers said that while small and large deletions are easy to find, mid-size deletions could be missed. Or, it is possible—though unlikely—that the mutation is not even in the SNP-defined region, Rademakers suggested. In a so-called synthetic association, the real marker of interest can be up to a megabase away from the associated SNPs.

Next-generation sequencing will surely be part of the ensuing mutation hunt. High-throughput sequencing through the entire region, with good bioinformatics and cooperation between groups, is the best way forward, Al-Chalabi wrote in an e-mail to ARF.

What clinicians would like is a genetic test they could use for diagnosis and genetic counseling, said Adam Boxer of the University of California in San Francisco, who was not involved in the current studies. With all of this convergent information, we may be getting to that point, he said. And, he hopes, mutation identification will yield clues to the disease process and potential treatments. Whatever this [mutation] is, I think it is going to tell us a lot about TDP-43 proteinopathies and what the mechanism might be, he said.

Shatunov A, Mok K, Newhouse S, Weale M, Smith B, Vance C, Johnson L, Veldink JH, van Es MA, van den Berg LH, Robberecht W, Van Damme P, Hardiman O, Farmer AE, Lewis CM, Butler AW, Abel O, Andersen PM, Fogh I, Silani V, Chi A, Traynor BJ, Melki J, Meininger V, Landers JE, McGuffin P, Glass JD, Pall H, Leigh PN, Hardy J, Brown RH Jr, Powell JF, Orrell RW, Morrison KE, Shaw PJ, Shaw CE, Al-Chalabi A. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genomewide association study. Lancet Neurol. 2010 Aug 27. Abstract

Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, Myllykangas L, Sulkava R, Jansson L, Hernandez D, Gibbs JR, Nalls MA, Heckerman D, Tienarit PJ, Traynor BJ. Chromosome 9p12 in amyotrophic lateral sclerosis in Finland: a genomewide association study. Lancet Neurol. 2010 Aug 27. Abstract

Daoud H, Belzil V, Dion PA, Rouleau GA. Chromosome 9p21 in amyotrophic lateral sclerosis: the plot thickens. Lancet Neurol. 2010 Aug 27. Abstract

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