ALS Consortium of Epidemiologic Studies (ACES)

Genetics of ALS

Genetic susceptibility is an important determinant of the risk for ALS, and is the topic of several excellent reviews (1-4). ALS presents a broad range of heritability from sporadic ALS (sALS) to families with multiple cases of ALS (fALS), consistent with an autosomal pattern of Mendelian inheritance. Clinic based studies have estimated that 10% of ALS cases are familial, although population-based studies suggest that the prevalence of fALS is 1.5% to 5% (5-7). Patients with familial ALS are on average 15 to 20 years younger than patients diagnosed with sporadic ALS and tend to have distinctive phenotypes (8). A major breakthrough was achieved in 1993 with the discovery that mutations of the superoxide dismutase (SOD1) gene account for 20% of familial ALS cases (9). In total, over 125 mutations of the SOD1 gene have been observed, with 114 mutations considered pathogenic for ALS (1). Unknown factors must be contributing to the penetrance of the SOD1 mutations because not all SOD1 carriers develop fALS. To date, clinical progression or other aspects of disease phenotype have not been correlated with SOD1 enzyme activity (10-12). Other Mendelian genes have been identified that are responsible for even fewer cases of fALS. These include Alsin (ALS2) (13,14), senataxin (SETX) (15,16), VAMP-associated protein B (VAPB) (17) and dynactin (DCTN1) (18). Additional genes for ALS have been localized on several chromosomes (15, 16, 18, 20 and X) (19-24) and with frontotemporal dementia (ALS-FTD) (25,26).

To better understand the pathogenesis of ALS, the focus has turned to the identification of genetic factors associated with sporadic ALS. Associations between common variants (polymorphisms, copy number variants) of specific genes and the risk of ALS have been identified in recent candidate gene studies. These genes include angiogenin (ANG) (27), vascular-endothelial growth factor (VEGF) (28,29), SMN1 and SMN2 (30,31), and apurinic/apyrimidinic exonuclease (APEX) (32). However, as is typical of candidate gene studies of chronic diseases, many studies have failed to replicate initial positive associations with these putative candidate genes (2, 4).

Mutations in the hemochromatosis (HFE) gene can disrupt iron metabolism and may increase the risk of ALS (33,34). Several studies have examined the association of a functional variant (H63D) in the HFE gene with ALS (34-37). Three of the four studies reported a twofold increase in risk of ALS with the H63D variant (35-37). After pooling results from all previous studies, carriers of the H63D allele were found to have an increased risk of ALS (heterozygote carrier OR 1.5, 95% CI 1.0-2.1; homozygote carrier OR 2.7, 95% CI 1.7-4.4) (37).

Paraoxonase (PON) is a serum enzyme involved in the detoxification of organophosphate insecticides. Saeed et al. (38) reported that a haploblock of high linkage disequilibrium spanning PON2 and PON3 was associated with SALS. Investigators from Poland carried out a case-control study and reported that PON1 (Q192R) and PON2 (C311S) were significantly associated with increased risk of ALS (39). A more recent study in Ireland found that two low functioning variants of the PON1 gene were associated with sALS, and a two locus haplotype analysis showed association only when both of these risk alleles were present (OR 1.7, p = 0.005) (40). Some epidemiologic studies have identified associations between pesticide exposure and ALS, therefore, it would be of considerable interest to determine whether PON polymorphisms modify the risk associated with pesticide exposure.

Polymorphisms in the genes for ?-aminolevulinic acid dehydratase (ALAD) may affect susceptibility to lead exposure. In a case-control study conducted in New England, Kamel et al. (41) reported that cases had higher blood and bone lead levels, with a 1.9-fold increase in risk for each µg/dl increment in blood lead. A polymorphism in the ALAD gene was also associated with a 1.9-fold increase in ALS risk; however, the investigators did not find evidence that the ALAD polymorphism modified the strength of the association of lead with ALS (42). As this was the only study to investigate the possible association of ALAD with ALS risk, it is an intriguing finding that requires replication, especially given the consistency of studies implicating lead exposure in ALS.

Several genome-wide association studies were recently undertaken in the USA (43-45), the Netherlands (46) and Ireland (47) to identify genetic loci that increase the risk of ALS. The study from the Netherlands identified two genetic variants that were associated with ALS (46,48), one in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) and the other in the dipeptidyl peptidase (DPP6) gene. ITPR2 is a calcium channel blocker that controls intracellular concentrations of calcium in motor neurons (49,50) and DPP6 regulates the biological activity of the neuropeptides (51,52). Mutations of ITPR2 can increase calcium concentrations, which can lead to apoptosis and degeneration of motor neurons. The Dutch investigators combined samples from two other studies for a total of 1337 ALS cases and 1356 controls (40) and reported an association between the ITRP2 variant and ALS (OR = 1.6, 95% CI 1.3-1.9). Mutations of DPP6 may affect binding of potassium channels and alter protein expression. Combining DNA samples from three other studies (1767 ALS cases and 1916 controls), the Dutch investigators reported a 30% increase in the risk of ALS with the DPP6 variant (OR = 1.3, 95% CI1.2-1.4) (48). Copy-number variants were also screened in one genome-wide study (53). Although none of the common copy-number variants were associated with sALS, cases had a higher number of deleted genes (40%) compared to the control subjects (16%), suggesting a possible role of gene deletions in the pathogenesis of ALS.

               Genetics References:
  1. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 2006;7:710-723.
  2. Schymick JC, Talbot K, Traynor BJ. Genetics of sporadic amyotrophic lateral sclerosis. Hum Mol Genet 2007;16 (Spec No. 2):R233-R242.
  3. Valdmanis P, Rouleau GA. Genetics of amyotrphic lateral sclerosis. Neurology 2008;70:144-152.
  4. Simpson CL, Al-Chalabi A. Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta 2006;1762(11-12):973-785. PMID:
  5. Logroscino G, Beghi E, Zoccolella V, Serlenga, L. Incidence of amyotrophic lateral sclerosis in southern Italy : a population-based study. J Neurol Neurosurg Psychiatry 2005;76:.1094-1098.
  6. Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (PARALS). Incidence of ALS in Italy: evidence for a uniform frequency in Western countries. Neurology 2001;56: 239-244.
  7. Yoshida S, Mulder DW, Kurland LT, Chu CP, Okazaki H. Follow-up study on amyotrophic lateral sclerosis in Rochester, Minnesota, 1925-1984. Neuroepidemiology 1986;5:61-70.
  8. Chiò A, Brignolio F, Meineri P, Schiffer D.  Phenotypic and genotypic heterogeneity of dominantly inherited amyotrophic lateral sclerosis.  Acta Neurol Scand 1987;75:277-282.
  9. Siddique T, Figlewicz DA, Pericak-Vance MA, Haines JL, Rouleau G, Jeffers AJ, Sapp P, Hung WY, Bebout J, McKenna-Yasek D et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med 1991;324:1381-1384.
  10. Andersen PM, Nilsson P, Keränen ML, Forsgren L, Hägglund J, Karlsborg M, Ronnevi LO, Gredal O, Marklund SL. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain 1997;120:1723-1737.
  11. Radunovic A, Delves HT, Robberecht W, Tilkin P, Enayat ZE, Shaw CE, Stevic Z, Apostolski S, Powell JF, Leigh PN. Copper and zinc levels in familial amyotrophic lateral sclerosis patients with CuZnSOD gene mutations. Ann Neurol 1997;42:130-131.
  12. Yamanaka K, Cleveland DW. Determinants of rapid disease progression in ALS. Neurology 2005;65:1859-1860.
  13. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 2001;29:160-165.
  14. Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001;29:166-173.
  15. Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, Griffin JW, Cornblath DR. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet 1998;62:633-640.
  16. Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004;74:1128-1135.
  17. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004;75:822-831.
  18. Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH Jr, Ludlow CL, Fischbeck KH. Mutant dynactin in motor neuron disease. Nat Genet 2003;33:455-456.
  19. Ruddy DM, Parton MJ, Al-Chalabi A, Lewis CM, Vance C, Smith BN, Leigh PN, Powell JF, Siddique T, Meyjes EP, Baas F, de Jong V, Shaw CE. Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am J Hum Genet 2003;73:390-396.
  20. Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yang Y, Rimmler J, Hung W, Schlotter B, Ahmed A, Ben Hamida M, Hentati F, Siddique T. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998;2:55-60.
  21. Sapp PC, Rosen DR, Hosler BA, Esteban J, McKenna-Yasek D, O'Regan JP, Horvitz HR, Brown RH Jr. Identification of three novel mutations in the gene for Cu/Zn superoxide dismutase in patients with familial amyotrophic lateral sclerosis. Neuromuscul Disord 1995;5:353-357.
  22. Abalkhail H, Mitchell J, Habgood J, Orrell R, de Belleroche J. A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1-16q12.2. Am J Hum Genet 2003;73:383-399.
  23. Siddique T, Hong ST, Brooks BR. X-linked dominant locus for late-onset familial amyotrophic lateral sclerosis. Am J Human Genet 1998;63(Suppl):A308.
  24. Hand CK, Khoris J, Salachas F, Gros-Louis F, Lopes AA, Mayeux-Portas V, Brewer CG, Brown RH Jr, Meininger V, Camu W, Rouleau GA. A novel locus for familial amyotrophic lateral sclerosis on chromosome 18q. Am J Hum Genet 2002;70:251-256. Erratum in: Am J Hum Genet 2002;71(4):1007.
  25. 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 Jr. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006;66:839-44.
  26. Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, Daube JR, Nance M, Fan C, Kaplan J, Hung WY, McKenna-Yasek D, Haines JL, Pericak-Vance MA, Horvitz HR, Brown RH Jr. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 2000;284:1664-1669.
  27. Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr, Hardiman O. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet 2006;38:411-3.
  28. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001;28:131-13.
  29. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004;429:413-417.
  30. Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, Lummen C, Scheffer H, Wokke JH, Van den Berg LH. SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology 2005;65:820-825.
  31. Corcia P, Camu W, Halimi JM, Vourc'h P, Antar C, Vedrine S, Giraudeau B, de Toffol B, Andres CR; French ALS Study Group. SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology 2006;67:1147-1150.
  32. Hayward C, Colville S, Swingler RJ, Brock DJ. Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis. Neurology 1999;52:1899-1901.
  33. Wang XS, Lee S, Simmons Z, Boyer P, Scott K, Liu W, Connor J. Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences. J Neurol Sci 2004;227:27-33.
  34. Yen AA, Simpson EP, Henkel JS, Beers DR, Appel SH. HFE mutations are not strongly associated with sporadic ALS. Neurology 2004;62:1611-1612.
  35. Wang X, Lee S, Simmons Z, et al. Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related consequences. J Neurol Sci 2004;227:27-33.
  36. Goodall EF, Greenway MJ, van Marion I, Carroll CB, Hardiman O, Morrison KE. Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS. Neurology 2005;65:934-937.
  37. Sutedja NA, Sinke RJ, Van Vught PW, Van der Linden MW, Wokke JH, Van Duijn CM, Njajou OT, Van der Schouw YT, Veldink JH, Van den Berg LH. The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population. Arch Neurol 2007;64:63-67.
  38. Saeed M, Siddique N, Hung WY, Usacheva E, Liu E, Sufit RL, Heller SL, Haines JL, Pericak-Vance M, Siddique T. Paraoxonase cluster polymorphisms are associated with sporadic ALS. Neurology 2006;67:771-776.
  39. Slowik A, Tomik B, Wolkow PP, Partyka D, Turaj W, Malecki MT, Pera J, Dziedzic T, Szczudlik A, Figlewicz DA. Paraoxonase gene polymorphisms and sporadic ALS. Neurology 2006;67:766-770.
  40. Cronin S, Greenway MJ, Prehn JH, Hardiman O. Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2007;78:984-986.
  41. Kamel F, Umbach DM, Hu H, Munsat TL, Shefner JM, Taylor JA, Sandler DP. Lead exposure as a risk factor for amyotrophic lateral sclerosis. Neurodegener Dis 2005;2:195-201.
  42. Kamel F, Umbach DM, Lehman TA, Park LP, Munsat TL, Shefner JM, Sandler DP, Hu H, Taylor JA. Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. Environ Health Perspect 2003;111:1335-1339.
  43. 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, Chiņ 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;6:322-328.
  44. 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;357:775-788.
  45. Kasperaviciute D, Weale ME, Shianna KV, Banks GT, Simpson CL, Hansen VK, Turner MR, Shaw CE, Al-Chalabi A, Pall HS, Goodall EF, Morrison KE, Orrell RW, Beck M, Jablonka S, Sendtner M, Brockington A, Ince PG, Hartley J, Nixon H, Shaw PJ, Schiavo G, Wood NW, Goldstein DB, Fisher EM. Large-scale pathways-based association study in amyotrophic lateral sclerosis. Brain 2007;130:2292-2301.
  46. 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;6:869-77.
  47. 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;17:768-774.
  48. 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;40:29-31.
  49. Mikoshiba K. Inositol 1,4,5-triphosphate (IP)3 receptors and their role in neuronal cell function. J Neurochem 2006;97:1627-1633.
  50. Boehning D, Patterson RL, Snyder SH. Apoptosis and calcium: new roles for cytochrome c and inositol 1,4,5-triphosphate. Cell Cycle 2004;3:252-254.
  51. Tachibana T, Noguchi K, Ruda MA. Analysis of gene expression following spinal cord injury in rat using complementary DNA microarray. Neurosci Lett 2002;327(2):133-137.
  52. Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 2004;119:1027-40.
  53. Blauw HM, Veldink JH, van Es MA, van Vught PW, Saris CG, van der Zwaag B, Franke L, Burbach JP, Wokke JH, Ophoff RA, van den Berg LH. Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen. Lancet Neuro 2008;7:319-326.

Footer Links: