Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2005 May;76(5):623–631. doi: 10.1136/jnnp.2004.047704

Neurogenetics II: complex disorders

A Wright 1
PMCID: PMC1739632  PMID: 15834017

Abstract

The genetic analysis of common neurological disorders will be a difficult and protracted endeavour. Genetics is only one of many disciplines that will be required but it has already thrown considerable light on the aetiology of several major neurological disorders through the analysis of rare inherited subgroups. The identification of individual susceptibility genes with variants of smaller effect will be more difficult but there is no sharp demarcation between large and small genetic effects, so that many new and important insights will emerge using existing and new technologies. The availability of improved neuroimaging, better animal models of disease and new genetic tools, such as high-throughput gene chips, expression microarrays and proteomics, are extending the range of traditional genetic mapping tools. Finally, an understanding of the genetic and epigenetic mechanisms that restrain the differentiation and integration of human neural stem cells into mature neuronal networks could have a major impact on clinical practice. These approaches will be illustrated in the context of Alzheimer disease, Parkinson disease and synucleinopathies, tauopathies, amyotrophic lateral sclerosis and stroke.

Full Text

The Full Text of this article is available as a PDF (184.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen Maxine, Heinzmann Andrea, Noguchi Emiko, Abecasis Gonçalo, Broxholme John, Ponting Chris P., Bhattacharyya Sumit, Tinsley Jon, Zhang Youming, Holt Richard. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet. 2003 Oct 19;35(3):258–263. doi: 10.1038/ng1256. [DOI] [PubMed] [Google Scholar]
  2. Bales K. R., Verina T., Dodel R. C., Du Y., Altstiel L., Bender M., Hyslop P., Johnstone E. M., Little S. P., Cummins D. J. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997 Nov;17(3):263–264. doi: 10.1038/ng1197-263. [DOI] [PubMed] [Google Scholar]
  3. Bentley David R. Genomes for medicine. Nature. 2004 May 27;429(6990):440–445. doi: 10.1038/nature02622. [DOI] [PubMed] [Google Scholar]
  4. Bergem A. L., Engedal K., Kringlen E. The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry. 1997 Mar;54(3):264–270. doi: 10.1001/archpsyc.1997.01830150090013. [DOI] [PubMed] [Google Scholar]
  5. Bertram Lars, Tanzi Rudolph E. Alzheimer's disease: one disorder, too many genes? Hum Mol Genet. 2004 Feb 5;13(SPEC):R135–R141. doi: 10.1093/hmg/ddh077. [DOI] [PubMed] [Google Scholar]
  6. Blomqvist Mia E-L, Silburn Peter A., Buchanan Daniel D., Andreasen Niels, Blennow Kaj, Pedersen Nancy L., Brookes Anthony J., Mellick George D., Prince Jonathan A. Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease. Neurogenetics. 2004 Apr 16;5(2):115–119. doi: 10.1007/s10048-004-0173-4. [DOI] [PubMed] [Google Scholar]
  7. Bonifati Vincenzo, Rizzu Patrizia, van Baren Marijke J., Schaap Onno, Breedveld Guido J., Krieger Elmar, Dekker Marieke C. J., Squitieri Ferdinando, Ibanez Pablo, Joosse Marijke. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2002 Nov 21;299(5604):256–259. doi: 10.1126/science.1077209. [DOI] [PubMed] [Google Scholar]
  8. Botstein David, Risch Neil. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet. 2003 Mar;33 (Suppl):228–237. doi: 10.1038/ng1090. [DOI] [PubMed] [Google Scholar]
  9. Bruijn L. I., Becher M. W., Lee M. K., Anderson K. L., Jenkins N. A., Copeland N. G., Sisodia S. S., Rothstein J. D., Borchelt D. R., Price D. L. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997 Feb;18(2):327–338. doi: 10.1016/s0896-6273(00)80272-x. [DOI] [PubMed] [Google Scholar]
  10. Butte Atul. The use and analysis of microarray data. Nat Rev Drug Discov. 2002 Dec;1(12):951–960. doi: 10.1038/nrd961. [DOI] [PubMed] [Google Scholar]
  11. Caillier S., Barcellos L. F., Baranzini S. E., Swerdlin A., Lincoln R. R., Steinman L., Martin E., Haines J. L., Pericak-Vance M., Hauser S. L. Osteopontin polymorphisms and disease course in multiple sclerosis. Genes Immun. 2003 Jun;4(4):312–315. doi: 10.1038/sj.gene.6363952. [DOI] [PubMed] [Google Scholar]
  12. Carlson Christopher S., Eberle Michael A., Kruglyak Leonid, Nickerson Deborah A. Mapping complex disease loci in whole-genome association studies. Nature. 2004 May 27;429(6990):446–452. doi: 10.1038/nature02623. [DOI] [PubMed] [Google Scholar]
  13. Caughey Byron, Lansbury Peter T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003 Apr 9;26:267–298. doi: 10.1146/annurev.neuro.26.010302.081142. [DOI] [PubMed] [Google Scholar]
  14. Dahlman Ingrid, Eaves Iain A., Kosoy Roman, Morrison V. Anne, Heward Joanne, Gough Stephen C. L., Allahabadia Amit, Franklyn Jayne A., Tuomilehto Jaakko, Tuomilehto-Wolf Eva. Parameters for reliable results in genetic association studies in common disease. Nat Genet. 2002 Jan 22;30(2):149–150. doi: 10.1038/ng825. [DOI] [PubMed] [Google Scholar]
  15. Delacourte A., David J. P., Sergeant N., Buée L., Wattez A., Vermersch P., Ghozali F., Fallet-Bianco C., Pasquier F., Lebert F. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology. 1999 Apr 12;52(6):1158–1165. doi: 10.1212/wnl.52.6.1158. [DOI] [PubMed] [Google Scholar]
  16. Dilda Christy L., Mackay Trudy F. C. The genetic architecture of Drosophila sensory bristle number. Genetics. 2002 Dec;162(4):1655–1674. doi: 10.1093/genetics/162.4.1655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Eriksson P. S., Perfilieva E., Björk-Eriksson T., Alborn A. M., Nordborg C., Peterson D. A., Gage F. H. Neurogenesis in the adult human hippocampus. Nat Med. 1998 Nov;4(11):1313–1317. doi: 10.1038/3305. [DOI] [PubMed] [Google Scholar]
  18. Ertekin-Taner Nilüfer, Allen Mariet, Fadale Daniel, Scanlin Leah, Younkin Linda, Petersen Ronald C., Graff-Radford Neill, Younkin Steven G. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat. 2004 Apr;23(4):334–342. doi: 10.1002/humu.20016. [DOI] [PubMed] [Google Scholar]
  19. Ertekin-Taner Nilüfer, Ronald James, Asahara Hideaki, Younkin Linda, Hella Maria, Jain Shushant, Gnida Eugene, Younkin Samuel, Fadale Daniel, Ohyagi Yasumasa. Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Hum Mol Genet. 2003 Oct 14;12(23):3133–3143. doi: 10.1093/hmg/ddg343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Farris Wesley, Mansourian Stefan, Chang Yang, Lindsley Loren, Eckman Elizabeth A., Frosch Matthew P., Eckman Christopher B., Tanzi Rudolph E., Selkoe Dennis J., Guenette Suzanne. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003 Mar 12;100(7):4162–4167. doi: 10.1073/pnas.0230450100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Farris Wesley, Mansourian Stefan, Leissring Malcolm A., Eckman Elizabeth A., Bertram Lars, Eckman Christopher B., Tanzi Rudolph E., Selkoe Dennis J. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol. 2004 Apr;164(4):1425–1434. doi: 10.1016/s0002-9440(10)63229-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fearnley J. M., Lees A. J. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 1991 Oct;114(Pt 5):2283–2301. doi: 10.1093/brain/114.5.2283. [DOI] [PubMed] [Google Scholar]
  23. Fullerton Jan, Cubin Matthew, Tiwari Hemant, Wang Chenxi, Bomhra Amarjit, Davidson Stuart, Miller Sue, Fairburn Christopher, Goodwin Guy, Neale Michael C. Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am J Hum Genet. 2003 Feb 20;72(4):879–890. doi: 10.1086/374178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Galvin J. E., Lee V. M., Trojanowski J. Q. Synucleinopathies: clinical and pathological implications. Arch Neurol. 2001 Feb;58(2):186–190. doi: 10.1001/archneur.58.2.186. [DOI] [PubMed] [Google Scholar]
  25. Ginsberg S. D., Hemby S. E., Lee V. M., Eberwine J. H., Trojanowski J. Q. Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons. Ann Neurol. 2000 Jul;48(1):77–87. [PubMed] [Google Scholar]
  26. Goldberg M. S., Lansbury P. T., Jr Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease? Nat Cell Biol. 2000 Jul;2(7):E115–E119. doi: 10.1038/35017124. [DOI] [PubMed] [Google Scholar]
  27. Gretarsdottir Solveig, Thorleifsson Gudmar, Reynisdottir Sigridur Th, Manolescu Andrei, Jonsdottir Sif, Jonsdottir Thorbjörg, Gudmundsdottir Thorunn, Bjarnadottir Sigrun M., Einarsson Olafur B., Gudjonsdottir Herdis M. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003 Sep 21;35(2):131–138. doi: 10.1038/ng1245. [DOI] [PubMed] [Google Scholar]
  28. Hall J. M., Lee M. K., Newman B., Morrow J. E., Anderson L. A., Huey B., King M. C. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990 Dec 21;250(4988):1684–1689. doi: 10.1126/science.2270482. [DOI] [PubMed] [Google Scholar]
  29. Hardy John, Selkoe Dennis J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353–356. doi: 10.1126/science.1072994. [DOI] [PubMed] [Google Scholar]
  30. Hebert Liesi E., Scherr Paul A., Bienias Julia L., Bennett David A., Evans Denis A. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003 Aug;60(8):1119–1122. doi: 10.1001/archneur.60.8.1119. [DOI] [PubMed] [Google Scholar]
  31. Helgadottir Anna, Manolescu Andrei, Thorleifsson Gudmar, Gretarsdottir Solveig, Jonsdottir Helga, Thorsteinsdottir Unnur, Samani Nilesh J., Gudmundsson Gudmundur, Grant Struan F. A., Thorgeirsson Gudmundur. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004 Feb 8;36(3):233–239. doi: 10.1038/ng1311. [DOI] [PubMed] [Google Scholar]
  32. Humphries Steve E., Morgan Laleh. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol. 2004 Apr;3(4):227–235. doi: 10.1016/S1474-4422(04)00708-2. [DOI] [PubMed] [Google Scholar]
  33. Hutton M., Lendon C. L., Rizzu P., Baker M., Froelich S., Houlden H., Pickering-Brown S., Chakraverty S., Isaacs A., Grover A. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702–705. doi: 10.1038/31508. [DOI] [PubMed] [Google Scholar]
  34. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y., Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998 Apr 9;392(6676):605–608. doi: 10.1038/33416. [DOI] [PubMed] [Google Scholar]
  35. Kruglyak L., Nickerson D. A. Variation is the spice of life. Nat Genet. 2001 Mar;27(3):234–236. doi: 10.1038/85776. [DOI] [PubMed] [Google Scholar]
  36. LaDu M. J., Pederson T. M., Frail D. E., Reardon C. A., Getz G. S., Falduto M. T. Purification of apolipoprotein E attenuates isoform-specific binding to beta-amyloid. J Biol Chem. 1995 Apr 21;270(16):9039–9042. doi: 10.1074/jbc.270.16.9039. [DOI] [PubMed] [Google Scholar]
  37. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  38. Leissring Malcolm A., Farris Wesley, Chang Alice Y., Walsh Dominic M., Wu Xining, Sun Xiaoyan, Frosch Matthew P., Selkoe Dennis J. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003 Dec 18;40(6):1087–1093. doi: 10.1016/s0896-6273(03)00787-6. [DOI] [PubMed] [Google Scholar]
  39. Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., Brownstein M. J., Jonnalagada S., Chernova T. The ubiquitin pathway in Parkinson's disease. Nature. 1998 Oct 1;395(6701):451–452. doi: 10.1038/26652. [DOI] [PubMed] [Google Scholar]
  40. Li Yi-Ju, Oliveira Sofia A., Xu Puting, Martin Eden R., Stenger Judith E., Scherzer Clemens R., Hauser Michael A., Scott William K., Small Gary W., Nance Martha A. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003 Oct 21;12(24):3259–3267. doi: 10.1093/hmg/ddg357. [DOI] [PubMed] [Google Scholar]
  41. Liu Yichin, Fallon Lara, Lashuel Hilal A., Liu Zhihua, Lansbury Peter T., Jr The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002 Oct 18;111(2):209–218. doi: 10.1016/s0092-8674(02)01012-7. [DOI] [PubMed] [Google Scholar]
  42. Lockhart D. J., Barlow C. Expressing what's on your mind: DNA arrays and the brain. Nat Rev Neurosci. 2001 Jan;2(1):63–68. doi: 10.1038/35049070. [DOI] [PubMed] [Google Scholar]
  43. Lubec Gert, Krapfenbauer Kurt, Fountoulakis Michael. Proteomics in brain research: potentials and limitations. Prog Neurobiol. 2003 Feb;69(3):193–211. doi: 10.1016/s0301-0082(03)00036-4. [DOI] [PubMed] [Google Scholar]
  44. Mahley R. W., Rall S. C., Jr Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507–537. doi: 10.1146/annurev.genom.1.1.507. [DOI] [PubMed] [Google Scholar]
  45. Maries Eleonora, Dass Biplob, Collier Timothy J., Kordower Jeffrey H., Steece-Collier Kathy. The role of alpha-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci. 2003 Sep;4(9):727–738. doi: 10.1038/nrn1199. [DOI] [PubMed] [Google Scholar]
  46. Martin E. R., Gilbert J. R., Lai E. H., Riley J., Rogala A. R., Slotterbeck B. D., Sipe C. A., Grubber J. M., Warren L. L., Conneally P. M. Analysis of association at single nucleotide polymorphisms in the APOE region. Genomics. 2000 Jan 1;63(1):7–12. doi: 10.1006/geno.1999.6057. [DOI] [PubMed] [Google Scholar]
  47. Mayeux R., Saunders A. M., Shea S., Mirra S., Evans D., Roses A. D., Hyman B. T., Crain B., Tang M. X., Phelps C. H. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. N Engl J Med. 1998 Feb 19;338(8):506–511. doi: 10.1056/NEJM199802193380804. [DOI] [PubMed] [Google Scholar]
  48. Mayeux Richard. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003 Jan 24;26:81–104. doi: 10.1146/annurev.neuro.26.043002.094919. [DOI] [PubMed] [Google Scholar]
  49. Mirnics K., Middleton F. A., Marquez A., Lewis D. A., Levitt P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron. 2000 Oct;28(1):53–67. doi: 10.1016/s0896-6273(00)00085-4. [DOI] [PubMed] [Google Scholar]
  50. Nagy Z., Esiri M. M., Jobst K. A., Morris J. H., King E. M., McDonald B., Litchfield S., Smith A., Barnetson L., Smith A. D. Relative roles of plaques and tangles in the dementia of Alzheimer's disease: correlations using three sets of neuropathological criteria. Dementia. 1995 Jan-Feb;6(1):21–31. doi: 10.1159/000106918. [DOI] [PubMed] [Google Scholar]
  51. Niino Masaaki, Kikuchi Seiji, Fukazawa Toshiyuki, Yabe Ichiro, Tashiro Kunio. Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. J Neuroimmunol. 2003 Mar;136(1-2):125–129. doi: 10.1016/s0165-5728(03)00004-3. [DOI] [PubMed] [Google Scholar]
  52. Polymeropoulos M. H., Lavedan C., Leroy E., Ide S. E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997 Jun 27;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  53. Prince Jonathan A., Feuk Lars, Gu Harvest F., Johansson Boo, Gatz Margaret, Blennow Kaj, Brookes Anthony J. Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Hum Mutat. 2003 Nov;22(5):363–371. doi: 10.1002/humu.10282. [DOI] [PubMed] [Google Scholar]
  54. Pritchard J. K. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001 Jun 12;69(1):124–137. doi: 10.1086/321272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Raber J., Wong D., Yu G. Q., Buttini M., Mahley R. W., Pitas R. E., Mucke L. Apolipoprotein E and cognitive performance. Nature. 2000 Mar 23;404(6776):352–354. doi: 10.1038/35006165. [DOI] [PubMed] [Google Scholar]
  56. Rakic Pasko. Neuroscience: immigration denied. Nature. 2004 Feb 19;427(6976):685–686. doi: 10.1038/427685a. [DOI] [PubMed] [Google Scholar]
  57. Reich D. E., Lander E. S. On the allelic spectrum of human disease. Trends Genet. 2001 Sep;17(9):502–510. doi: 10.1016/s0168-9525(01)02410-6. [DOI] [PubMed] [Google Scholar]
  58. Rosen D. R., Siddique T., Patterson D., Figlewicz D. A., Sapp P., Hentati A., Donaldson D., Goto J., O'Regan J. P., Deng H. X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. doi: 10.1038/362059a0. [DOI] [PubMed] [Google Scholar]
  59. Rosso Sonia M., van Swieten John C. New developments in frontotemporal dementia and parkinsonism linked to chromosome 17. Curr Opin Neurol. 2002 Aug;15(4):423–428. doi: 10.1097/00019052-200208000-00004. [DOI] [PubMed] [Google Scholar]
  60. Sanai Nader, Tramontin Anthony D., Quiñones-Hinojosa Alfredo, Barbaro Nicholas M., Gupta Nalin, Kunwar Sandeep, Lawton Michael T., McDermott Michael W., Parsa Andrew T., Manuel-García Verdugo José. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004 Feb 19;427(6976):740–744. doi: 10.1038/nature02301. [DOI] [PubMed] [Google Scholar]
  61. St George-Hyslop P. H. Molecular genetics of Alzheimer's disease. Biol Psychiatry. 2000 Feb 1;47(3):183–199. doi: 10.1016/s0006-3223(99)00301-7. [DOI] [PubMed] [Google Scholar]
  62. Steinman Lawrence, Zamvil Scott. Transcriptional analysis of targets in multiple sclerosis. Nat Rev Immunol. 2003 Jun;3(6):483–492. doi: 10.1038/nri1108. [DOI] [PubMed] [Google Scholar]
  63. Wright A. F., Carothers A. D., Pirastu M. Population choice in mapping genes for complex diseases. Nat Genet. 1999 Dec;23(4):397–404. doi: 10.1038/70501. [DOI] [PubMed] [Google Scholar]
  64. Wright Alan, Charlesworth Brian, Rudan Igor, Carothers Andrew, Campbell Harry. A polygenic basis for late-onset disease. Trends Genet. 2003 Feb;19(2):97–106. doi: 10.1016/s0168-9525(02)00033-1. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES