44 Parent-Child Trios Yield 40 Candidate ALS Genes

Scientists have identified 40 genes that might contain rare mutations that cause amyotrophic lateral sclerosis. The authors of a paper in the March 16 Scientific Reports found these candidate ALS genes by sequencing DNA of 44 ALS patients and their healthy parents. Using child-and-parents “trio” analyses allowed the researchers to identify rare genetic variants that likely cause disease in the children, said first author Karyn Meltz Steinberg of the Washington University School of Medicine in St. Louis. Researchers will need to confirm these results with additional studies, she said.

Sporadic ALS results from a combination of genetic and environmental risk factors. Genome-wide association studies can point to common risk variants that associate with diseases. However, researchers have not been able to confirm many ALS gene candidates with this approach (see Feb 2009 news). As an alternative strategy, a couple of research groups have turned to genetic trios. Scientists studying complex diseases, such as autism, have used trios to find genetic mutations that appear in a child, but not in either parent (Fukai et al., 2015; O’Roak et al., 2012). Roger Pamphlett of the University of Sydney showed it could work for ALS in a pilot study that identified copy-number variants, but not sequence changes, in the offspring, and not the parents, of a dozen trios (Pamphlett et al., 2011). In a separate project, Aaron Gitler and colleagues at Stanford University in Palo Alto, California, used trios to identify de novo mutations in 25 candidate ALS genes (see May 2013 news).

Compared with early onset conditions such as autism, the trio approach presents a challenge for diseases, like as ALS, that typically start in late middle age. “It is very difficult to find trios where both parents are unaffected, still alive, and consent to genetic studies,” Meltz Steinberg said. Pamphlett, the senior author, told Alzforum it took him 10 years to scour all of Australia for the 44 trios in this study. Even at that, it was difficult to find trios with people who developed ALS later in life. The average age at onset in the study was 46, compared to 62 for all people with sporadic ALS represented in the Australian Motor Neuron Disease DNA Bank. Several families had parents younger than 70, meaning some of those parents might still go on to develop ALS, making their child’s disease familial, not sporadic, noted Marka van Blitterswijk of the Mayo Clinic in Jacksonville, Florida, who was not involved in the study. However, she added that the authors could not avoid this caveat.

Pamphlett and Meltz Steinberg sequenced the exomes of all trio members and looked for two kinds of variants: recessive mutations and de novo changes. For the analysis of recessive variants, Meltz Steinberg looked for children who had inherited the same variant from both parents, or a different variant from each parent but in the same gene. She focused only on extremely rare variants found in 1 percent or fewer of the world population. She also limited her list to variants predicted to alter protein function. This analysis led her to variants in 23 candidate genes. In the case of de novo variants, not occurring in either parent, Meltz Steinberg found mutations in the coding sequence of 17 genes.

To figure out how these 40 genes might contribute to motor neuron disease, Meltz Steinberg examined their functions. Some of the genes code for proteins that participate in transcriptional regulation, as do known ALS genes like TDP-43 and FUS. Others are involved in cell-cycle management, which was implicated in the disease by at least one other study (Ranganathan and Bowser, 2003). A handful of the genes coded for dynein-like domains; mutations in the dynein cytoskeletal motor lead to ALS-like symptoms in mice (see May 2003 news). One would expect to see at least some overlap between these results and earlier findings from Gitler and colleagues, commented Ekaterina Rogaeva of the University of Toronto, who was not part of either study. However, Gitler’s study reported genes involved in neurite outgrowth and chromatin remodeling. The lack of concordance makes it difficult to interpret the findings, Rogaeva said.

One common gene emerged. Both trio studies identified de novo mutations in cholinergic receptor, muscarinic 1 (CHRM1). The CHRM1 receptor has been linked to neurodegeneration in mice that model Alzheimer’s disease. Deleting the gene exacerbates cognitive deficiencies and plaque pathology in APP/PS/tau triple transgenic (3xTG) mice and APP (TgSwDI) mice (Medeiros et al., 2011). “I was not surprised, but I was reassured that we found a de novo variant in the same gene reported in the Gitler paper,” Meltz Steinberg said. “That suggested we were onto something.”

Another gene on Meltz Steinberg’s list that has already appeared in ALS literature was inositol 1,4,5-triphosphate receptor, type 2 (ITPR2). The receptor forms a calcium channel on the endoplasmic reticulum of motor neurons. One genome-wide association study suggested ITPR2 might be a risk gene for ALS (van Es et al., 2007), but others have not replicated the result (Fernández et al., 2011; Chiò et al., 2009). The study authors pointed out that genome-wide association studies search for common variants, while the new work suggests that rare mutations in IPTR2 might underlie some ALS.

Both van Blitterswijk and Rogaeva said that trio studies were an important genetic tool, but the report left them wondering which genes really contribute to ALS and wishing for more follow-up. “They have a very interesting gene list,” van Blitterswijk said. “It is hard to interpret what is a real [ALS variant] and what is not.” She speculated that some of those variants might be associated with neurodegenerative diseases in general, and not ALS specifically.

Others might not be disease-associated at all. “We each have many changes in our DNA that our parents do not have, and in most cases, these changes do not cause us problems,” wrote Summer Gibson of the University of Utah School of Medicine in Salt Lake City, who did not participate in the work, in an email to Alzforum. Indeed, the study authors noted that some of their genes are known to vary often in exome-sequencing studies. Gibson cautioned, “There have been many gene candidates for ALS, a large number of which have not turned out to be real.”

To narrow this list to the true contributors, Rogaeva suggested sequencing more people with ALS, looking for an excess of variants in any of the 40 candidates compared to control genomes. Meltz Steinberg agreed the candidates are currently unconfirmed, and said she and Pamphlett do plan to look for variants in these genes in other people with ALS.—Amber Dance

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References

News Citations

  1. Genomewide Screen for SNPs Linked to Sporadic ALS Finds…Nothing Yet
  2. The Power of Three: Genetic Trios Yield ALS Gene Candidates
  3. Role of the Motor in Motor Neuron Diseases

Research Models Citations

  1. 3xTg
  2. Tg-SwDI (APP-Swedish,Dutch,Iowa)

Paper Citations

  1. Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, Tanaka F, Miyake N, Matsumoto N. A case of autism spectrum disorder arising from a de novo missense mutation in POGZ. J Hum Genet. 2015 Feb 19; PubMed.
  2. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012 May 10;485(7397):246-50. PubMed.
  3. Pamphlett R, Morahan JM, Yu B. Using case-parent trios to look for rare de novo genetic variants in adult-onset neurodegenerative diseases. J Neurosci Methods. 2011 Apr 30;197(2):297-301. Epub 2011 Mar 15 PubMed.
  4. Ranganathan S, Bowser R. Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am J Pathol. 2003 Mar;162(3):823-35. PubMed.
  5. Medeiros R, Kitazawa M, Caccamo A, Baglietto-Vargas D, Estrada-Hernandez T, Cribbs DH, Fisher A, Laferla FM. Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline. Am J Pathol. 2011 Aug;179(2):980-91. PubMed.
  6. 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.
  7. 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.
  8. 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.

External Citations

  1. cholinergic receptor, muscarinic 1 (CHRM1)
  2. inositol 1,4,5-triphosphate receptor, type 2 (ITPR2)

Further Reading

Papers

  1. Ajroud-Driss S, Siddique T. Sporadic and hereditary amyotrophic lateral sclerosis (ALS). Biochim Biophys Acta. 2015 Apr;1852(4):679-684. Epub 2014 Sep 1 PubMed.
  2. Laferriere F, Polymenidou M. Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis. Swiss Med Wkly. 2015;145:w14054. Epub 2015 Jan 30 PubMed.
  3. He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA. Amyotrophic Lateral Sclerosis Genetic Studies: From Genome-wide Association Mapping to Genome Sequencing. Neuroscientist. 2014 Nov 5; PubMed.
  4. Carlesi C, CaldarazzoIenco E, Mancuso M, Siciliano G. Amyotrophic Lateral Sclerosis: A Genetic Point Of View. Curr Mol Med. 2014 Oct 10; PubMed.
  5. Leblond CS, Kaneb HM, Dion PA, Rouleau GA. Dissection of genetic factors associated with amyotrophic lateral sclerosis. Exp Neurol. 2014 Apr 26; PubMed.

Primary Papers

  1. Steinberg KM, Yu B, Koboldt DC, Mardis ER, Pamphlett R. Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS. Sci Rep. 2015 Mar 16;5:9124. PubMed.

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