14 Feb 2009

The hunt is on for genetic variants that increase risk of sporadic amyotrophic lateral sclerosis—but the searchers are coming back empty-handed. That is likely due to the heterogeneity of the disease, conclude the authors of the largest genomewide association study to date, published online February 4 in Human Molecular Genetics. The variability of ALS, both clinically and genetically, means scientists are searching for needles in a whole field full of haystacks. But researchers have not given up hope; with single nucleotide polymorphisms collected from enough subjects, they may yet succeed. The International Consortium on Amyotrophic Lateral Sclerosis Genetics, sponsored by the ALS Association (ALSA), is working to collect thousands of subjects by archiving and analyzing SNP data in one large repository.

“Everyone wants to find the ApoE equivalent for their disease,” said John Trojanowski of the University of Pennsylvania in Philadelphia, who was not involved with the current genomewide association study (GWAS). These types of investigations have identified many risk factors for conditions such as Alzheimer’s and diabetes (see AlzGene). In ALS, Trojanowski said, the negative results of screens so far indicate that “whatever the genetic contributions are, they’re all weak and widely distributed across the genome.”

First author Adriano Chiò of the University of Turin, Italy, and senior author Bryan Traynor of the National Institute on Aging in Bethesda, Maryland, and colleagues collected data on 545,066 SNPs from 553 people with ALS and 2,338 control individuals. From that initial screen, they selected 7,600 SNPs for further analysis in three separate groups that totaled 2,160 people with ALS and 3,008 controls. None of those SNPs met the most rigorous statistical tests for significance.

The study, then, failed to replicate loci that earlier GWA screens had picked out as potential links to ALS. These include FGGY, ITPR2, and DPP6 (Dunckley et al., 2007; van Es et al., 2007; Cronin et al., 2008; van Es et al., 2008; and see ARF related news story). That means those loci are unlikely to be truly related to ALS, Traynor said.

Traynor suspects that the current study did not use a large enough group of subjects in the first phase of the research. “It was rather a coarse sieve,” he said. “It’s quite possible that something would have slipped through our fingers.” Amassing the biggest data set possible is the premise behind the International Consortium. Run by Lucie Bruijn, senior vice president for research and development at ALSA, which is headquartered in Calabasas Hills, California, the project was founded in 2008 and includes several investigators involved in ALS genetics research. So far, the database has collected nearly 2,500 ALS cases and 3,500 controls, and is aiming for thousands more. ALSA has also hired an independent statistician to analyze the results pooled from the different labs. Making these data broadly available, Traynor said, will help speed up the search. SNP data for other diseases, such as Alzheimer’s and Parkinson’s, are also increasingly being shared (see related ARF Live Discussion).

Another approach, Traynor said, is to search in a population that is fairly similar, genetically speaking. If all study participants have a low rate of genetic variability, then that decreases the rate of false positives in a GWAS. Traynor, along with Simon Cronin and Orla Hardiman of Beaumont Hospital in Dublin, Ireland, tried this strategy with the Irish population in a study published last year in Human Molecular Genetics. Situated on the far edge of Europe, Ireland has hosted fewer migrants than other countries, and for much of its history laws restricted travel, so the scientists suspected the genetic homogeneity of the island would make the search easier. Their top hit was DPP6, which was not confirmed in the current publication. The Irish study probably failed to pull out relevant SNPs because it only included 221 cases, Traynor said. Traynor, who is Irish, also noted that “it turns out we are a little bit more heterogeneous than we like to believe…that’s probably because we’ve been invaded by everybody but Genghis Khan.” Next, Traynor has set his sights on Finland, another genetically homogeneous population that also has a high rate of ALS, he said.

Although the current study found no SNPs that crossed the threshold into statistical significance, it yielded two hits of interest to the authors. Both were located on chromosome 7p13.3, in a linkage group containing the genes SUNC1, HUS1, and C7orf57. The most significant SNP was within an intron of SUNC1, making that gene the most likely candidate—although Traynor cautioned that sometimes an SNP can act as a reporter for a gene far from its locus. SUNC1’s biological function also makes it an appealing suspect. It encodes the nuclear envelope protein “Sad1 and UNC84 domain containing 1,” and mutations in other nuclear envelope genes are known to cause neuromuscular diseases including Charcot-Marie-Tooth disease (De Sandre-Giovannoli et al., 2002) and spastin-associated hereditary spastic paraplegia (Hazan et al., 1999). That said, Traynor and his coauthors are the first to admit that the evidence for SUNC1’s role is weak, and needs to be confirmed in another study.

“It is most important that the community is not disheartened by the lack of early success in these initial GWASs on ALS,” Cronin, who was not involved in the current GWAS, wrote in an e-mail to ARF. “Aside from one or two notable exceptions, all successful GWA studies have required several thousand cases and controls in the discovery phase.”

While geneticists bemoan the heterogeneity of ALS, pathologists are buoyed by the similarities between the condition and another disease, frontotemporal lobar degeneration. Writing in the February Archives of Neurology, Trojanowski and first author Felix Geser, also at the University of Pennsylvania, describe TDP-43 pathology in postmortem analysis of people who had either disorder, or a mixed syndrome that incorporated symptoms of both ALS and FTLD. Trojanowski and others suspect that the two diseases lie at opposite ends of a spectrum of TDP-43 proteinopathies (see ARF related news story), and the current study supports that theory. “We kind of knew the answer, but we needed to do the work to show that it was indeed right,” Trojanowski said. “It’s bringing two disparate clinical phenotypes into the same mechanistic bucket.”

Analyzing the brains and spinal cords of their subjects, the UPenn scientists found that the location of the TDP-43 inclusions paralleled a person’s symptoms: people with ALS had TDP-43 in the spinal cord and people with FTLD had it in the brain. “In the brain, just like in real estate, location is everything,” Trojanowski said. He has no idea, he said, why TDP-43 accumulates in different locations in different people.

So, can ALS be both the same disease as FTLD, and yet so heterogeneous that no genetic risk factor for the spontaneous form has been confirmed? “These studies are not mutually exclusive,” wrote Kristel Sleegers and Christine Van Broeckhoven, both of the University of Antwerp, Belgium, in an e-mail to ARF. “Mutations in different genes can bring about similar phenotypes…. The challenge lies in identifying the factors that link the different elements in this continuum.” It will take more work to define what, exactly, ALS truly is.—Amber Dance

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References

News Citations

1. Sporadic ALS Linked to Potassium Channel 19 Dec 2007
2. Heady Times for Researchers Studying TDP-43 21 Apr 2008

Webinar Citations

1. Whole Genome Study for Parkinson Disease 13 Dec 2006

Paper Citations

1. 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.
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. 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.
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. De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N, Szepetowski P, Hammadouche T, Vandenberghe A, Stewart CL, Grid D, Lévy N. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002 Mar;70(3):726-36. PubMed.
6. Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Dürr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder JM, Prud'homme JF, Brice A, Fontaine B, Heilig B, Weissenbach J. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. 1999 Nov;23(3):296-303. PubMed.

External Citations

1. AlzGene

Further Reading

Papers

1. Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, Xie SX, Lee VM, Trojanowski JQ. Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol. 2008 May;65(5):636-41. PubMed.
2. Kwong LK, Uryu K, Trojanowski JQ, Lee VM. TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis. Neurosignals. 2008;16(1):41-51. PubMed.
3. Fung HC, Scholz S, Matarin M, Simón-Sánchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodríguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 2006 Nov;5(11):911-6. PubMed.
4. Marx J. Neurodegenerative diseases. Picking apart the causes of mysterious dementias. Science. 2006 Oct 6;314(5796):42-3. PubMed.

News

1. Research Brief: Redefining ALS—Time to Think Laterally? 23 May 2008
2. New Database Connects Gene Expression, Disease 1 Oct 2006
3. Sporadic ALS Linked to Potassium Channel 19 Dec 2007
4. Heady Times for Researchers Studying TDP-43 21 Apr 2008