A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

Human Molecular Genetics

Volumn 22, Issue 4, 2013, Pages 816-824

  Chapman, Jade ^a   Rees, Elliott ^a   Harold, Denise ^a   Ivanov, Dobril ^a   Gerrish, Amy ^a   Sims, Rebecca ^a   Hollingworth, Paul ^a   Stretton, Alexandra ^a   Holmans, Peter ^a   Owen, Michael J ^a   O'Donovan, Michael C ^a   Williams, Julie ^a   Kirov, George ^a  

^a CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADULT; AGED; ALZHEIMER DISEASE; ARTICLE; BIPOLAR DISORDER; CLINICAL ASSESSMENT; CONTROLLED STUDY; COPY NUMBER VARIATION; GENE DELETION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; HUMAN; MAJOR CLINICAL STUDY; PRIORITY JOURNAL; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM;

AGED; ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; CASE-CONTROL STUDIES; DNA COPY NUMBER VARIATIONS; GENE DUPLICATION; GENETIC LOCI; GENETIC PREDISPOSITION TO DISEASE; GENOME, HUMAN; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HUMANS; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTORS, COMPLEMENT 3B; RISK FACTORS;

EID: 84873051400     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/dds476     Document Type: Article

References (53)

1. Jones, L., Harold, D. and Williams, J. (2010) Genetic evidence for the involvement of lipid metabolism in Alzheimer's disease. Biochim. Biophys. Acta, 1801, 754-761.
2. Avramopoulos, D. (2009) Genetics of Alzheimer's disease: recent advances. Genome Med., 1, 34.
3. Saunders, A.M., Strittmatter, W.J., Schmechel, D., George-Hyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper- MacLachlan, D.R., Alberts, M.J. et al. (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology, 43, 1467-1472.
4. Bertram, L., Lange, C., Mullin, K., Parkinson, M., Hsiao, M., Hogan, M.F., Schjeide, B.M., Hooli, B., Divito, J., Ionita, I. et al. (2008) Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet., 83, 623-632.
5. Hollingworth, P., Harold, D., Jones, L., Owen, M.J. and Williams, J. (2010) Alzheimer's disease genetics: current knowledge and future challenges. Int. J. Geriatr. Psychiatry, 26, 793-802.
6. Naj, A.C., Jun, G., Beecham, G.W., Wang, L.S., Vardarajan, B.N., Buros, J., Gallins, P.J., Buxbaum, J.D., Jarvik, G.P., Crane, P.K. et al. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet., 43, 436-441.
7. Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, J.C., Carrasquillo, M.M., Abraham, R., Hamshere, M.L., Pahwa, J.S., Moskvina, V. et al. (2011) Common variants at ABCA7, MS4A6A/ MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet., 43, 429-435.
8. Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M.L., Pahwa, J.S., Moskvina, V., Dowzell, K., Williams, A. et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet., 41, 1088-1093.
9. Lambert, J.C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M.J., Tavernier, B. et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet., 41, 1094-1099.
10. Seshadri, S., Fitzpatrick, A.L., Ikram, M.A., DeStefano, A.L., Gudnason, V., Boada, M., Bis, J.C., Smith, A.V., Carassquillo, M.M., Lambert, J.C. et al. (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA, 303, 1832-1840.
11. Lee, J.A. and Lupski, J.R. (2006) Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron, 52, 103-121.
12. O'Donovan, M.C., Kirov, G. and Owen, M.J. (2008) Phenotypic variations on the theme of CNVs. Nat. Genet., 40, 1392-1393.
13. McCarthy, S.E., Makarov, V., Kirov, G., Addington, A.M., McClellan, J., Yoon, S., Perkins, D.O., Dickel, D.E., Kusenda, M., Krastoshevsky, O. et al. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet., 41, 1223-1227.
14. Kirov, G. (2010) The role of copy number variation in schizophrenia. Expert Rev. Neurother., 10, 25-32.
15. Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerriere, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M. et al. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet., 38, 24-26.
16. Heinzen, E.L., Need, A.C., Hayden, K.M., Chiba-Falek, O., Roses, A.D., Strittmatter, W.J., Burke, J.R., Hulette, C.M., Welsh-Bohmer, K.A. and Goldstein, D.B. (2010) Genome-wide scan of copy number variation in late-onset Alzheimer's disease. J. Alzheimers Dis., 19, 69-77.
17. Swaminathan, S., Kim, S., Shen, L., Risacher, S.L., Foroud, T., Pankratz, N., Potkin, S.G., Huentelman, M.J., Craig, D.W., Weiner, M.W. et al. (2011) Genomic copy number analysis in Alzheimer's disease and mild cognitive impairment: an ADNI Study. Int. J. Alzheimers Dis., 2011, Article ID: 729478.
18. Swaminathan, S., Shen, L., Kim, S., Inlow, M., West, J.D., Faber, K.M., Foroud, T., Mayeux, R. and Saykin, A.J. (2012) Analysis of copy number variation in Alzheimer's disease: the NIA-LOAD/NCRAD Family Study. Curr. Alzheimer Res., 9, 801-814.
19. Ghani, M., Pinto, D., Lee, J.H., Grinberg, Y., Sato, C., Moreno, D., Scherer, S.W., Mayeux, R., St George-Hyslop, P. and Rogaeva, E. (2012) Genome-wide survey of large rare copy number variants in Alzheimer's disease among Caribbean hispanics. G3 (Bethesda), 2, 71-78.
20. ISC (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237-241.
21. Heinzen, E.L., Radtke, R.A., Urban, T.J., Cavalleri, G.L., Depondt, C., Need, A.C., Walley, N.M., Nicoletti, P., Ge, D., Catarino, C.B. et al. (2010) Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am. J. Hum. Genet., 86, 707-718.
22. Kirov, G., Grozeva, D., Norton, N., Ivanov, D., Mantripragada, K.K., Holmans, P., Craddock, N., Owen, M.J. and O'Donovan, M.C. (2009) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum. Mol. Genet., 18, 1497-1503.
23. Cooper, G.M., Coe, B.P., Girirajan, S., Rosenfeld, J.A., Vu, T.H., Baker, C., Williams, C., Stalker, H., Hamid, R., Hannig, V. et al. (2011) A copy number variation morbidity map of developmental delay. Nat. Genet., 43, 838-846.
24. Grozeva, D., Kirov, G., Ivanov, D., Jones, I.R., Jones, L., Green, E.K., St Clair, D.M., Young, A.H., Ferrier, N., Farmer, A.E. et al. (2010) Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch. Gen. Psychiatry, 67, 318-327.
25. McNaughton, D., Knight, W., Guerreiro, R., Ryan, N., Lowe, J., Poulter, M., Nicholl, D.J., Hardy, J., Revesz, T., Rossor, M. et al. (2010) Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series. Neurobiol. Aging, 44, 426.e413-426.e421.
26. Grozeva, D., Conrad, D.F., Barnes, C.P., Hurles, M., Owen, M.J., O'Donovan, M.C., Craddock, N. and Kirov, G. (2012) Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia. Schizophr. Res., 135, 1-7.
27. Jones, L., Holmans, P.A., Hamshere, M.L., Harold, D., Moskvina, V., Ivanov, D., Pocklington, A., Abraham, R., Hollingworth, P., Sims, R. et al. (2010) Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE, 5, e13950.
28. Holmans, P., Green, E.K., Pahwa, J.S., Ferreira, M.A., Purcell, S.M., Sklar, P., Owen, M.J., O'Donovan, M.C. and Craddock, N. (2009) Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. Am. J. Hum. Genet., 85, 13-24.
29. Williams, N.M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O.O. et al. (2010) Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet, 376, 1401-1408.
30. Guyant-Marechal, L., Rovelet-Lecrux, A., Goumidi, L., Cousin, E., Hannequin, D., Raux, G., Penet, C., Ricard, S., Mace, S., Amouyel, P. et al. (2007) Variations in the APP gene promoter region and risk of Alzheimer disease. Neurology, 68, 684-687.
31. Sleegers, K., Brouwers, N., Gijselinck, I., Theuns, J., Goossens, D., Wauters, J., Del-Favero, J., Cruts, M., van Duijn, C.M. and Van Broeckhoven, C. (2006) APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain, 129, 2977-2983.
32. Rovelet-Lecrux, A., Frebourg, T., Tuominen, H., Majamaa, K., Campion, D. and Remes, A.M. (2007) APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage. J. Neurol. Neurosurg. Psychiatry, 78, 1158-1159.
33. Kasuga, K., Shimohata, T., Nishimura, A., Shiga, A., Mizuguchi, T., Tokunaga, J., Ohno, T., Miyashita, A., Kuwano, R., Matsumoto, N. et al. (2009) Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J. Neurol. Neurosurg. Psychiatry, 80, 1050-1052.
34. Brouwers, N., Van Cauwenberghe, C., Engelborghs, S., Lambert, J.C., Bettens, K., Le Bastard, N., Pasquier, F., Montoya, A.G., Peeters, K., Mattheijssens, M. et al. (2012) Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol. Psychiatry, 17, 223-233.
35. Abe-Dohmae, S., Ikeda, Y., Matsuo, M., Hayashi, M., Okuhira, K., Ueda, K. and Yokoyama, S. (2004) Human ABCA7 supports apolipoproteinmediated release of cellular cholesterol and phospholipid to generate high density lipoprotein. J. Biol. Chem., 279, 604-611.
36. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. and Stadlan, E.M. (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology, 34, 939-944.
37. Mirra, S.S., Heyman, A., McKeel, D., Sumi, S.M., Crain, B.J., Brownlee, L.M., Vogel, F.S., Hughes, J.P., van Belle, G. and Berg, L. (1991) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology, 41, 479-486.
38. Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S.F., Hakonarson, H. and Bucan, M. (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res., 17, 1665-1674.
39. Kirov, G., Pocklington, A.J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., Moran, J., Chambert, K., Toncheva, D., Georgieva, L. et al. (2012) De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry, 17, 142-153.
40. Bailey, J.A., Yavor, A.M., Massa, H.F., Trask, B.J. and Eichler, E.E. (2001) Segmental duplications: organization and impact within the current human genome project assembly. Genome Res., 11, 1005-1017.
41. Bailey, J.A., Gu, Z., Clark, R.A., Reinert, K., Samonte, R.V., Schwartz, S., Adams, M.D., Myers, E.W., Li, P.W. and Eichler, E.E. (2002) Recent segmental duplications in the human genome. Science, 297, 1003-1007.
42. WTCCC(2010) Genome-wide association study ofCNVsin 16,000 cases of eight common diseases and 3,000 shared controls. Nature, 464, 713-720.
43. Rees, E., Moskvina, V., Owen, M.J., O'Donovan, M.C. and Kirov, G. (2011) De novo rates and selection of schizophrenia-associated copy number variants. Biol. Psychiatry, 70, 1109-1114.
44. Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Sklar, P., de Bakker, P.I., Daly, M.J. et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet., 81, 559-575.
45. Kirov, G., Rujescu, D., Ingason, A., Collier, D.A., O'Donovan, M.C. and Owen, M.J. (2009) Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr. Bull., 35, 851-854.
46. Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E. et al. (2009) Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet., 18, 988-996.
47. Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T. et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet., 25, 25-29.
48. Subramanian, A., Tamayo, P., Mootha, V.K., Mukherjee, S., Ebert, B.L., Gillette, M.A., Paulovich, A., Pomeroy, S.L., Golub, T.R., Lander, E.S. et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA, 102, 15545-15550.
49. Raychaudhuri, S., Korn, J.M., McCarroll, S.A., Altshuler, D., Sklar, P., Purcell, S. and Daly, M.J. (2010) Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet., 6, e1001097.
50. Storey, J.D. and Tibshirani, R. (2003) Statistical significance for genomewide studies. Proc. Natl Acad. Sci. USA, 100, 9440-9445.
51. Benjamini, Y. and Hochberg, Y. (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Stat. Methodol., 57, 289-300.
52. Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., le Roux, L., Gustafsson, O., Craddock, N. et al. (2011) Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. Am. J. Psychiatry, 168, 408-417.
53. Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P. et al. (2011) Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol. Psychiatry, 16, 17-25.