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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