03 May 2013

Researchers using genomewide screens have identified two new loci for sporadic amyotrophic lateral sclerosis genes in the Han Chinese population. As reported in the April 28 Nature Genetics online, the two single nucleotide polymorphisms (SNPs) do not appear to associate with the disease in either new or previously reported datasets from people of European ancestry. Likewise, several variants associated with ALS in genomewide association studies (GWAS) of Europeans failed to turn up in the Han Chinese cohort, reports a research team led by first author Min Deng of Peking University Third Hospital in Beijing, and senior author Kai Wang of the First Affiliated Hospital of Anhui Medical University in Hefei, also in China. The results suggest that the molecular basis of ALS may be different between the two populations.

To study the Han Chinese, who number 1.2 billion and are the largest ethnic group in China, the research team initiated a GWAS in 506 people with sporadic ALS and 1,859 control cases. They picked out 90 top SNP variants from that study and then performed a second analysis examining those, plus six variants previously identified in European GWAS (ITPR2, FLJ10988, DPP6, UNC13A, MOBKL2B, and C9ORF72). In this second cohort, with 706 ALS patients and 1,777 controls, the researchers found that two new SNPs passed stringent statistical hurdles for association with ALS. These two polymorphisms explain about 12 percent of sporadic ALS in Han Chinese, the authors estimate. One of the variants, on chromosome 1, boosted a person’s risk of ALS by 31 percent, while the second, on chromosome 22, amplified ALS chances by 52 percent.

None of the six previously identified ALS risk variants associated with disease in the new analysis, suggesting different genetic risk profiles among Chinese and Europeans. However, of those six variants, only C9ORF72 has been reliably confirmed, noted Faisal Fecto of the Northwestern University Feinberg School of Medicine in Chicago, Illinois. Fecto was not involved with the Chinese study. The other five variants might turn out to be important to the populations in which they were discovered, or they might just be false positives, Fecto said (see ARF related news story on Chiò et al., 2009; also Chen et al., 2012).

As for the new variants, Fecto said that the replication performed by the authors in Han Chinese is convincing, but does not tell if these SNPs have anything to do with ALS in other populations. The authors looked for these new variants in novel and previously published genetic data from Europeans (van Es et al., 2007; van Es et al., 2008; van Es et al., 2009), but could not find any link with ALS. An association might still be present, Fecto noted, but at too low a level to show up in the studies.

More intriguingly, "It could be that European ALS is truly genetically distinct from Han Chinese ALS, at least in cases driven by these two particular variants," said Dietrich Stephan of Silicon Valley Biosystems, Inc., in Foster City, California. This kind of variation between groups of different ancestry is not uncommon, added Stephan, who was not an author on the paper. Supporting this notion, the authors report that ALS in their Han Chinese cohort differs somewhat from that in Europeans. The age of onset tended to be about 10 years earlier—averaging 48-49 in the Chinese, versus 59 in Europeans. The Chinese study participants were also 15 percent more likely to have the disease start in their limbs, as opposed to the mouth and throat. About 87 percent of Chinese experience their first weakness in the limbs, compared to 71 percent of Europeans. “The differences in ALS clinical characteristics between the two populations may result from ancestry-related heterogeneity,” the authors conclude.

While identifying a SNP is not the same as identifying a cause, the researchers speculate on how the variants contribute to disease. The chromosome 1 variant sits near the gene for Ca2+/calmodulin-dependent protein kinase I γ (CaMKIγ), a nervous system-specific kinase (Takemoto-Kimura et al., 2003). This gene makes a plausible suspect because it is the only one in the vicinity, Fecto said. CaM kinases are involved in learning, memory, synaptic plasticity, and dendritic development, he noted. He speculated that CaMKIγ might also play a role in frontotemporal dementia, which often coincides with ALS symptoms and shares genetic causes.

The study authors note CaMKIγ signaling involves brain-derived neurotrophic factor (BDNF; Takemoto-Kimura et al., 2007), which promotes neuron survival. CaMKI proteins and related kinases also protect neurons from apoptosis (Yano et al., 1998), and the authors speculate that CaMKIγ might do the same. If that is so, then mutations in the gene might make neurons particularly sensitive to apoptosis.

The other SNP lies near three genes, and upon further examination the authors found 34 other SNPs in the region that also correlated with ALS risk. That makes it difficult to guess which of the three genes, if any, contribute to the disease, Fecto said. One, calcineurin binding protein 1 (CABIN1), is widely expressed and involved in T cell signaling. Another codes for γ-glutamyl transferase 5 (GGT5), a membrane enzyme involved in several metabolic and biosynthetic pathways. The study authors favor the third—sushi domain containing 2 (SUSD2), a tumor suppressor involved in apoptosis signaling (Sugahara et al., 2007). The ALS SNP first identified in the study is predicted to substitute a serine for an asparagine in SUSD2. Mutations in the same domain as that substitution have been shown to promote apoptosis (Sugahara et al., 2007), leading the authors to conjecture that the variant may lead to ALS via neuron death. “It is certainly a plausible theory,” said Stephan, speculating that ALS-prone neurons might have a lower threshold for apoptosis than normal ones. Overall, this study provides one more step to understanding the complex, heterogeneous biology of sporadic ALS, Stephan said.—Amber Dance

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References

News Citations

1. Genomewide Screen for SNPs Linked to Sporadic ALS Finds…Nothing Yet 14 Feb 2009

Paper Citations

1. Chiò A, Schymick JC, Restagno G, Scholz SW, Lombardo F, Lai SL, Mora G, Fung HC, Britton A, Arepalli S, Gibbs JR, Nalls M, Berger S, Kwee LC, Oddone EZ, Ding J, Crews C, Rafferty I, Washecka N, Hernandez D, Ferrucci L, Bandinelli S, Guralnik J, Macciardi F, Torri F, Lupoli S, Chanock SJ, Thomas G, Hunter DJ, Gieger C, Wichmann HE, Calvo A, Mutani R, Battistini S, Giannini F, Caponnetto C, Mancardi GL, La Bella V, Valentino F, Monsurrò MR, Tedeschi G, Marinou K, Sabatelli M, Conte A, Mandrioli J, Sola P, Salvi F, Bartolomei I, Siciliano G, Carlesi C, Orrell RW, Talbot K, Simmons Z, Connor J, Pioro EP, Dunkley T, Stephan DA, Kasperaviciute D, Fisher EM, Jabonka S, Sendtner M, Beck M, Bruijn L, Rothstein J, Schmidt S, Singleton A, Hardy J, Traynor BJ. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Apr 15;18(8):1524-32. PubMed.
2. Chen Y, Zeng Y, Huang R, Yang Y, Chen K, Song W, Zhao B, Li J, Yuan L, Shang HF. No association of five candidate genetic variants with amyotrophic lateral sclerosis in a Chinese population. Neurobiol Aging. 2012 Nov;33(11):2721.e3-5. PubMed.
3. 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.
4. 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.
5. 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.
6. Takemoto-Kimura S, Terai H, Takamoto M, Ohmae S, Kikumura S, Segi E, Arakawa Y, Furuyashiki T, Narumiya S, Bito H. Molecular cloning and characterization of CLICK-III/CaMKIgamma, a novel membrane-anchored neuronal Ca2+/calmodulin-dependent protein kinase (CaMK). J Biol Chem. 2003 May 16;278(20):18597-605. PubMed.
7. Takemoto-Kimura S, Ageta-Ishihara N, Nonaka M, Adachi-Morishima A, Mano T, Okamura M, Fujii H, Fuse T, Hoshino M, Suzuki S, Kojima M, Mishina M, Okuno H, Bito H. Regulation of dendritogenesis via a lipid-raft-associated Ca2+/calmodulin-dependent protein kinase CLICK-III/CaMKIgamma. Neuron. 2007 Jun 7;54(5):755-70. PubMed.
8. Yano S, Tokumitsu H, Soderling TR. Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Nature. 1998 Dec 10;396(6711):584-7. PubMed.
9. Sugahara T, Yamashita Y, Shinomi M, Yamanoha B, Iseki H, Takeda A, Okazaki Y, Hayashizaki Y, Kawai K, Suemizu H, Andoh T. Isolation of a novel mouse gene, mSVS-1/SUSD2, reversing tumorigenic phenotypes of cancer cells in vitro. Cancer Sci. 2007 Jun;98(6):900-8. PubMed.
10. Sugahara T, Yamashita Y, Shinomi M, Isobe Y, Yamanoha B, Iseki H, Takeda A, Okazaki Y, Kawai K, Suemizu H, Andoh T. von Willebrand factor type D domain mutant of SVS-1/SUSD2, vWD(m), induces apoptosis in HeLa cells. Cancer Sci. 2007 Jun;98(6):909-15. PubMed.

External Citations

1. ITPR2
2. DPP6
3. UNC13A

Further Reading

Papers

1. Koppers M, Groen EJ, van Vught PW, van Rheenen W, Witteveen E, van Es MA, Pasterkamp RJ, van den Berg LH, Veldink JH. Screening for rare variants in the coding region of ALS-associated genes at 9p21.2 and 19p13.3. Neurobiol Aging. 2012 Nov 8; PubMed.
2. Li XG, Zhang JH, Xie MQ, Liu MS, Li BH, Zhao YH, Ren HT, Cui LY. Association between DPP6 polymorphism and the risk of sporadic amyotrophic lateral sclerosis in Chinese patients. Chin Med J (Engl). 2009 Dec 20;122(24):2989-92. PubMed.
3. Fogh I, D'Alfonso S, Gellera C, Ratti A, Cereda C, Penco S, Corrado L, Sorarù G, Castellotti B, Tiloca C, Gagliardi S, Cozzi L, Lupton MK, Ticozzi N, Mazzini L, Shaw CE, Al-Chalabi A, Powell J, Silani V. No association of DPP6 with amyotrophic lateral sclerosis in an Italian population. Neurobiol Aging. 2011 May;32(5):966-7. PubMed.
4. 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.
5. Fernández-Santiago R, Sharma M, Berg D, Illig T, Anneser J, Meyer T, Ludolph A, Gasser T. No evidence of association of FLJ10986 and ITPR2 with ALS in a large German cohort. Neurobiol Aging. 2011 Mar;32(3):551.e1-4. PubMed.
6. Fricker SP. Nitric oxide scavengers as a therapeutic approach to nitric oxide mediated disease. Expert Opin Investig Drugs. 1999 Aug;8(8):1209-22. PubMed.
7. Fang DF, Zhang SS, Guo XY, Zeng Y, Yang Y, Zhou D, Shang HF. Clinical and genetic features of patients with sporadic amyotrophic lateral sclerosis in south-west China. Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):350-4. PubMed.

News

1. C9ORF72 Update: ALS Gene Is a Variable, and Global, Phenomenon 21 Jun 2012
2. Corrupt Code: DNA Repeats Are Common Cause for ALS and FTD 23 Sep 2011
3. ALS GWAS Confirm Chromosome 9 Risk Factor—But What Is It? 5 Sep 2010
4. Research Brief: Latest ALS GWAS Points to Loci on Chromosomes 9, 19 7 Sep 2009
5. Sporadic ALS Linked to Potassium Channel 19 Dec 2007
6. Genomewide Screen for SNPs Linked to Sporadic ALS Finds…Nothing Yet 14 Feb 2009