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 Université de Montréal 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.—Amber Dance

Comments

  1. I think it will be found that aquaporin 3 will be the item of interest (1).

    Aquaporin 3 is found in "normal skeletal myofibres" (2).

    I suspect it will be found that the problem is not a mutation, but something interfering with the normal proper function of the aqp3 channels.

    Aquaporin 3 is, in addition to being a water channel, also an arsenic transporter.

    Arsenic has been implicated in Alzheimer's in at least a few instances. For example, this statement appears in Reference 3 below:

    "Arsenic can induce apoptosis in cortical neurons of rats. This process is based on the activation of JNK3 and p38 MAPK by arsenic...[which] can activate p38 MAPK and JNK3...."

    And the title of the last paper speaks for itself: “Arsenic exposure may be a risk factor for Alzheimer's disease.”

    References:

    Mulders SM, Olde Weghuis D, van Boxtel JA, van Kessel AG, Echevarria M, van Os CH, Deen PM. Localization of the human gene for aquaporin 3 (AQP3) to chromosome 9, region p21-->p12, using fluorescent in situ hybridization. Cytogenet Cell Genet. 1996;72(4):303-5. PubMed.

    Wakayama Y, Jimi T, Inoue M, Kojima H, Shibuya S, Murahashi M, Hara H, Oniki H. Expression of aquaporin 3 and its localization in normal skeletal myofibres. Histochem J. 2002 Jun-Jul;34(6-7):331-7. PubMed.

    Baum L, Chan IH, Cheung SK, Goggins WB, Mok V, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Zee BC, Cheng W, Chan MH, Szeto S, Lui V, Tsoh J, Bush AI, Lam CW, Kwok T. Serum zinc is decreased in Alzheimer's disease and serum arsenic correlates positively with cognitive ability. Biometals. 2010 Feb;23(1):173-9. PubMed.

    Gharibzadeh S, Hoseini SS. Arsenic exposure may be a risk factor for Alzheimer's disease. J Neuropsychiatry Clin Neurosci. 2008 Fall;20(4):501. PubMed.

    View all comments by P.F. Jennings

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References

News Citations

  1. Chromosome 9 Teases With Cryptic ALS/FTLD Link
  2. Research Brief: Latest ALS GWAS Points to Loci on Chromosomes 9, 19
  3. Sporadic ALS Linked to Potassium Channel

Paper Citations

  1. Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M, Joris G, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, Cruts M. Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol. 2010 May;67(5):606-16. PubMed.
  2. van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, Lemmens R, Schelhaas HJ, Groen EJ, Huisman MH, van der Kooi AJ, de Visser M, Dahlberg C, Estrada K, Rivadeneira F, Hofman A, Zwarts MJ, van Doormaal PT, Rujescu D, Strengman E, Giegling I, Muglia P, Tomik B, Slowik A, Uitterlinden AG, Hendrich C, Waibel S, Meyer T, Ludolph AC, Glass JD, Purcell S, Cichon S, Nöthen MM, Wichmann HE, Schreiber S, Vermeulen SH, Kiemeney LA, Wokke JH, Cronin S, McLaughlin RL, Hardiman O, Fumoto K, Pasterkamp RJ, Meininger V, Melki J, Leigh PN, Shaw CE, Landers JE, Al-Chalabi A, Brown RH Jr, Robberecht W, Andersen PM, Ophoff RA, van den Berg LH. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct;41(10):1083-7. Epub 2009 Sep 6 PubMed.
  3. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, Jongjaroenprasert W, Horvitz HR, Gunnarsson LG, Brown RH. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology. 2006 Mar 28;66(6):839-44. PubMed.
  4. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, Shaw CE. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006 Apr;129(Pt 4):868-76. PubMed.
  5. Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, Feldman H, Hsiung GY, Rutherford N, Laluz V, Whitwell J, Foti D, McDade E, Molano J, Karydas A, Wojtas A, Goldman J, Mirsky J, Sengdy P, Dearmond S, Miller BL, Rademakers R. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry. 2011 Feb;82(2):196-203. PubMed.
  6. Valdmanis PN, Dupre N, Bouchard JP, Camu W, Salachas F, Meininger V, Strong M, Rouleau GA. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol. 2007 Feb;64(2):240-5. PubMed.
  7. Kere J. Human population genetics: lessons from Finland. Annu Rev Genomics Hum Genet. 2001;2:103-28. PubMed.
  8. Murros K, Fogelholm R. Amyotrophic lateral sclerosis in Middle-Finland: an epidemiological study. Acta Neurol Scand. 1983 Jan;67(1):41-7. PubMed.
  9. Cronin S, Berger S, Ding J, Schymick JC, Washecka N, Hernandez DG, Greenway MJ, Bradley DG, Traynor BJ, Hardiman O. A genome-wide association study of sporadic ALS in a homogenous Irish population. Hum Mol Genet. 2008 Mar 1;17(5):768-74. PubMed.
  10. Landers JE, Melki J, Meininger V, Glass JD, van den Berg LH, van Es MA, Sapp PC, van Vught PW, McKenna-Yasek DM, Blauw HM, Cho TJ, Polak M, Shi L, Wills AM, Broom WJ, Ticozzi N, Silani V, Ozoguz A, Rodriguez-Leyva I, Veldink JH, Ivinson AJ, Saris CG, Hosler BA, Barnes-Nessa A, Couture N, Wokke JH, Kwiatkowski TJ, Ophoff RA, Cronin S, Hardiman O, Diekstra FP, Leigh PN, Shaw CE, Simpson CL, Hansen VK, Powell JF, Corcia P, Salachas F, Heath S, Galan P, Georges F, Horvitz HR, Lathrop M, Purcell S, Al-Chalabi A, Brown RH. Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9004-9. PubMed.
  11. 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.
  12. van Es MA, van Vught PW, Blauw HM, Franke L, Saris CG, Van Den Bosch L, de Jong SW, de Jong V, Baas F, van't Slot R, Lemmens R, Schelhaas HJ, Birve A, Sleegers K, Van Broeckhoven C, Schymick JC, Traynor BJ, Wokke JH, Wijmenga C, Robberecht W, Andersen PM, Veldink JH, Ophoff RA, van den Berg LH. Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2008 Jan;40(1):29-31. PubMed.
  13. Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K, Halperin RF, Stamper C, Jensen KR, Letizia D, Hesterlee SE, Pestronk A, Levine T, Bertorini T, Graves MC, Mozaffar T, Jackson CE, Bosch P, McVey A, Dick A, Barohn R, Lomen-Hoerth C, Rosenfeld J, O'connor DT, Zhang K, Crook R, Ryberg H, Hutton M, Katz J, Simpson EP, Mitsumoto H, Bowser R, Miller RG, Appel SH, Stephan DA. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med. 2007 Aug 23;357(8):775-88. PubMed.
  14. 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.
  15. Beaver JE, Tasan M, Gibbons FD, Tian W, Hughes TR, Roth FP. FuncBase: a resource for quantitative gene function annotation. Bioinformatics. 2010 Jul 15;26(14):1806-7. PubMed.

External Citations

  1. Finnish Disease Heritage website

Further Reading

Papers

  1. Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C, Couratier P, Legallic S, Salachas F, Hannequin D, Decousus M, Lacomblez L, Guedj E, Golfier V, Camu W, Dubois B, Campion D, Meininger V, Brice A, French Clinical and Genetic Research Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar Degeneration with Motoneuron Disease. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. 2009 Apr;65(4):470-3. PubMed.
  2. Bogaert E, Goris A, Van Damme P, Geelen V, Lemmens R, van Es MA, van den Berg LH, Sleegers K, Verpoorten N, Timmerman V, De Jonghe P, Van Broeckhoven C, Traynor BJ, Landers JE, Brown RH, Glass JD, Al-Chalabi A, Shaw CE, Birve A, Andersen PM, Slowik A, Tomik B, Melki J, Robberecht W, Van Den Bosch L. Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis. Neurobiol Aging. 2012 Feb;33(2):418-20. PubMed.
  3. Sha Q, Zhang Z, Schymick JC, Traynor BJ, Zhang S. Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis. BMC Med Genet. 2009;10:86. PubMed.
  4. Cronin S, Tomik B, Bradley DG, Slowik A, Hardiman O. Screening for replication of genome-wide SNP associations in sporadic ALS. Eur J Hum Genet. 2009 Feb;17(2):213-8. PubMed.
  5. Cronin S, Hardiman O, Traynor BJ. Ethnic variation in the incidence of ALS: a systematic review. Neurology. 2007 Mar 27;68(13):1002-7. PubMed.
  6. Schymick JC, Yang Y, Andersen PM, Vonsattel JP, Greenway M, Momeni P, Elder J, Chiò A, Restagno G, Robberecht W, Dahlberg C, Mukherjee O, Goate A, Graff-Radford N, Caselli RJ, Hutton M, Gass J, Cannon A, Rademakers R, Singleton AB, Hardiman O, Rothstein J, Hardy J, Traynor BJ. Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes. J Neurol Neurosurg Psychiatry. 2007 Jul;78(7):754-6. PubMed.

Primary Papers

  1. Shatunov A, Mok K, Newhouse S, Weale ME, 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, Chiò A, Traynor BJ, Melki J, Meininger V, Landers JE, McGuffin P, Glass JD, Pall H, Leigh PN, Hardy J, Brown RH, 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 genome-wide association study. Lancet Neurol. 2010 Oct;9(10):986-94. PubMed.
  2. Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, Myllykangas L, Sulkava R, Jansson L, Hernandez DG, Gibbs JR, Nalls MA, Heckerman D, Tienari PJ, Traynor BJ. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010 Oct;9(10):978-85. PubMed.
  3. Daoud H, Belzil V, Dion PA, Rouleau GA. Chromosome 9p21 in amyotrophic lateral sclerosis: the plot thickens. Lancet Neurol. 2010 Oct;9(10):945-7. PubMed.

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