Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genome-wide association study of Alzheimer's disease with psychotic symptoms

Molecular Psychiatry volume 17, pages 1316–1327 (2012)Cite this article

Subjects

Abstract

Psychotic symptoms occur in ∼40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD–P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD–P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD–P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10−7) and within VSNL1 (rs4038131, P=5.9 × 10−7) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Hollingworth P, Harold D, Jones L, Owen MJ, Williams J . Alzheimer’s disease genetics: current knowledge and future challenges. Int J Geriatr Psychiatry 2011; 26: 793–802.

    Article  PubMed  Google Scholar 

  2. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2009; 41: 1088–1093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A et al. Association of CR1, CLU and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet 2010; 19: 3295–3301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang Q, Yu JT, Zhu QX, Zhang W, Wu ZC, Miao D et al. Complement receptor 1 polymorphisms and risk of late onset Alzheimer’s disease. Brain Res 2010; 1348: 216–221.

    Article  CAS  PubMed  Google Scholar 

  5. Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F et al. Replication of CLU, CR1, and PICALM associations with Alzheimer disease. Arch Neurol 2010; 67: 961–964.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ et al. Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 2010; 67: 1473–1484.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Biffi A, Anderson CD, Desikan RS, Sabuncu M, Cortellini L, Schmansky N et al. Genetic variation and neuroimaging measures in Alzheimer disease. Arch Neurol 2010; 67: 677–685.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010; 303: 1832–1840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM et al. Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 2011; 43: 429–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 2011; 43: 436–441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. O’Donovan MC, Craddock NJ, Owen MJ . Genetics of psychosis; insights from views across the genome. Hum Genet 2009; 126: 3–12.

    Article  PubMed  Google Scholar 

  13. Sweet RA, Nimgaonkar VL, Devlin B, Jeste DV . Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype. Mol Psychiatry 2003; 8: 383–392.

    Article  CAS  PubMed  Google Scholar 

  14. Ropacki SA, Jeste DV . Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry 2005; 162: 2022–2030.

    Article  PubMed  Google Scholar 

  15. Shin IS, Carter M, Masterman D, Fairbanks L, Cummings JL . Neuropsychiatric symptoms and quality of life in Alzheimer disease. Am J Geriatr Psychiatry 2005; 13: 469–474.

    Article  PubMed  Google Scholar 

  16. Wilkosz PA, Seltman HJ, Devlin B, Weamer EA, Lopez OL, Dekosky ST et al. Trajectories of cognitive decline in Alzheimer’s disease. Int Psychogeriatr 2010; 22: 281–290.

    Article  PubMed  Google Scholar 

  17. Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST . Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol 1999; 56: 1266–1272.

    Article  CAS  PubMed  Google Scholar 

  18. Hollingworth P, Hamshere ML, Holmans PA, O’Donovan MC, Sims R, Powell J et al. Increased familial risk and genomewide significant linkage for Alzheimer’s disease with psychosis. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 841–848.

    Article  CAS  PubMed  Google Scholar 

  19. Sweet RA, Nimgaonkar VL, Devlin B, Lopez OL, DeKosky ST . Increased familial risk of the psychotic phenotype of Alzheimer disease. Neurology 2002; 58: 907–911.

    Article  CAS  PubMed  Google Scholar 

  20. Bacanu SA, Devlin B, Chowdari KV, DeKosky ST, Nimgaonkar VL, Sweet RA . Heritability of psychosis in Alzheimer disease. Am J Geriatr Psychiatry 2005; 13: 624–627.

    Article  PubMed  Google Scholar 

  21. Sweet RA, Bennett DA, Graff-Radford NR, Mayeux R . Assessment and familial aggregation of psychosis in Alzheimer’s disease from the National Institute on Aging Late Onset Alzheimer’s Disease Family Study. Brain 2010; 133 (Part 4): 1155–1162.

    Article  PubMed  PubMed Central  Google Scholar 

  22. DeMichele-Sweet MA, Sweet RA . Genetics of psychosis in Alzheimer’s disease: a review. J Alzheimers Dis 2010; 19: 761–780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R et al. Genome wide association of familial late onset Alzheimer’s disease replicates BIN1 and CLU, and nominates CUGBP2 in interaction with APOE. PLoS Genet 2011; 7: e1001308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Demichele-Sweet MA, Kleia L, Devlin B, Ferrellb RE, Weamera EA, Emanuela JE et al. No association of psychosis in Alzheimer disease with neurodegenerative pathway genes. Neurobiol Aging 2011; 32: 555.e9–555.e11.

    Article  Google Scholar 

  25. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . 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 1984; 34: 939–944.

    Article  CAS  PubMed  Google Scholar 

  26. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991; 41: 479–486.

    Article  CAS  PubMed  Google Scholar 

  27. Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R . Analyses of the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study: implication of additional loci. Arch Neurol 2008; 65: 1518–1526.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Weamer EA, Emanuel JE, Varon D, Miyahara S, Wilkosz PA, Lopez OL et al. The relationship of excess cognitive impairment in MCI and early Alzheimer’s disease to the subsequent emergence of psychosis. Int Psychogeriatr 2009; 21: 78–85.

    Article  PubMed  Google Scholar 

  29. Lopez OL, DeKosky ST . Neuropathology of Alzheimer’s disease and mild cognitive impairment]. Rev Neurol 2003; 37: 155–163.

    CAS  PubMed  Google Scholar 

  30. Ganguli M, Dodge HH, Chen P, Belle S, DeKosky ST . Ten-year incidence of dementia in a rural elderly US community population: the MoVIES Project. Neurology 2000; 54: 1109–1116.

    Article  CAS  PubMed  Google Scholar 

  31. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J . The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308–2314.

    Article  CAS  PubMed  Google Scholar 

  32. Cummings JL . The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48 (5 Suppl 6): S10–S16.

    Article  CAS  PubMed  Google Scholar 

  33. Tariot PN, Mack JL, Patterson MB, Edland SD, Weiner MF, Fillenbaum G et al. The behavior rating scale for dementia of the consortium to establish a registry for Alzheimer’s disease. The behavioral pathology committee of the consortium to establish a registry for Alzheimer’s disease. Am J Psychiatry 1995; 152: 1349–1357.

    Article  CAS  PubMed  Google Scholar 

  34. Wilkosz PA, Kodavali C, Weamer EA, Miyahara S, Lopez OL, Nimgaonkar VL et al. Prediction of psychosis onset in Alzheimer disease: the role of depression symptom severity and the HTR2A T102C polymorphism. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 1054–1062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hollingworth P, Hamshere ML, Moskvina V, Dowzell K, Moore PJ, Foy C et al. Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer’s disease. J Am Geriatr Soc 2006; 54: 1348–1354.

    Article  PubMed  Google Scholar 

  36. Reisberg B, Ferris SH, de Leon MJ, Crook T . The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982; 139: 1136–1139.

    Article  CAS  PubMed  Google Scholar 

  37. Berg L . Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988; 24: 637–639.

    CAS  PubMed  Google Scholar 

  38. Folstein MF, Folstein SE, McHugh PR . ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

    Article  CAS  PubMed  Google Scholar 

  39. Kamboh MI, Barmada MM, Demirci FY, Minster RL, Carrasquillo MM, Pankratz VS et al. Genome-wide association analysis of age-at-onset in Alzheimer's disease. Mol Psychiatry 2011 (in press).

  40. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

    Article  CAS  PubMed  Google Scholar 

  41. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee AB, Luca D, Klei L, Devlin B, Roeder K . Discovering genetic ancestry using spectral graph theory. Genet Epidemiol 2010; 34: 51–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Willer CJ, Li Y, Abecasis GR . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010; 26: 2190–2191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Devlin B, Roeder K . Genomic control for association studies. Biometrics 1999; 55: 997–1004.

    Article  CAS  PubMed  Google Scholar 

  45. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 2009; 41: 1094–1099.

    Article  CAS  PubMed  Google Scholar 

  46. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.

    Article  PubMed  Google Scholar 

  48. Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. McMahon FJ, Akula N, Schulze TG, Muglia P, Tozzi F, Detera-Wadleigh SD et al. Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet 2010; 42: 128–131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cichon S, Muhleisen TW, Degenhardt FA, Mattheisen M, Miro X, Strohmaier J et al. Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am J Hum Genet 2011; 88: 372–381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–757.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Whitlock MC . Combining probability from independent tests: the weighted Z-method is superior to Fisher’s approach. J Evol Biol 2005; 18: 1368–1373.

    Article  CAS  PubMed  Google Scholar 

  53. Braunewell KH, Klein-Szanto AJ . Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca2+ -sensor proteins. Cell Tissue Res 2009; 335: 301–316.

    Article  CAS  PubMed  Google Scholar 

  54. Lee JM, Blennow K, Andreasen N, Laterza O, Modur V, Olander J et al. The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer disease patients. Clin Chem 2008; 54: 1617–1623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ et al. Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet 2008; 17: 1156–1168.

    Article  CAS  PubMed  Google Scholar 

  56. Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Marangoni S, Novello JC et al. Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis. J Neural Transm 2009; 116: 275–289.

    Article  CAS  PubMed  Google Scholar 

  57. Rule AD, de Andrade M, Matsumoto M, Mosley TH, Kardia S, Turner ST . Association between SLC2A9 transporter gene variants and uric acid phenotypes in African American and white families. Rheumatology (Oxford) 2011; 50: 871–878.

    Article  CAS  Google Scholar 

  58. Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40: 437–442.

    Article  CAS  PubMed  Google Scholar 

  59. Bowman GL, Shannon J, Frei B, Kaye JA, Quinn JF . Uric acid as a CNS antioxidant. J Alzheimers Dis 2010; 19: 1331–1336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yao JK, Reddy R, van Kammen DP . Reduced level of plasma antioxidant uric acid in schizophrenia. Psychiatry Res 1998; 80: 29–39.

    Article  CAS  PubMed  Google Scholar 

  61. Reddy R, Keshavan M, Yao JK . Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 2003; 62: 205–212.

    Article  PubMed  Google Scholar 

  62. Kam M, Massare J, Gallinger S, Kinzie J, Weaver D, Dingell JD et al. Peutz-Jeghers syndrome diagnosed in a schizophrenic patient with a large deletion in the STK11 gene. Dig Dis Sci 2006; 51: 1567–1570.

    Article  PubMed  Google Scholar 

  63. Lee CH, Liu CM, Wen CC, Chang SM, Hwu HG . Genetic copy number variants in sib pairs both affected with schizophrenia. J Biomed Sci 2010; 17: 2.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Demichele-Sweet MA, Lopez OL, Sweet RA . Psychosis in Alzheimer’s disease in the national Alzheimer’s disease coordinating center uniform data set: clinical correlates and association with apolipoprotein e. Int J Alzheimers Dis 2011; 2011: 926597.

    PubMed  PubMed Central  Google Scholar 

  65. Chu SH, Roeder K, Ferrell RE, Devlin B, DeMichele-Sweet MA, Kamboh MI et al. TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. Neurobiol Aging 2011 (in press).

  66. Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 234–239.

    Article  CAS  PubMed  Google Scholar 

  67. Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.

    CAS  PubMed  Google Scholar 

  68. Lettre G, Rioux JD . Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet 2008; 17 (R2): R116–R121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Craddock N, O’Donovan MC, Owen MJ . Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or “schizoaffective”) psychoses. Schizophr Bull 2009; 35: 482–490.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Moskvina V, Holmans P, Schmidt KM, Craddock N . Design of case-controls studies with unscreened controls. Ann Hum Genet 2005; 69 (Part 5): 566–576.

    Article  CAS  PubMed  Google Scholar 

  71. Kamboh MI, Minster RL, Demirci FY, Ganguli M, Dekosky ST, Lopez OL et al. Association of CLU and PICALM variants with Alzheimer’s disease. Neurobiol Aging 2010 (in press).

  72. Schjeide BM, Schnack C, Lambert JC, Lill CM, Kirchheiner J, Tumani H et al. The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. Arch Gen Psychiatry 2011; 68: 207–213.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

GERAD1: We thank the patients and families who took part in this research. The Cardiff University group was supported by the Wellcome Trust, Medical Research Council, Alzheimer's Research Trust and the Welsh Assembly Government. The Alzheimer's Research Trust also supported and funded DNA sample collections at the Institute of Psychiatry, Cambridge University, University of Nottingham and University of Belfast. The University of Belfast group are supported by the Alzheimer's Society, Alzheimer's Research Trust, Ulster Garden Villages, N Ireland R&D Office and the Royal College of Physicians/Dunhill Medical Trust. The Trinity College Dublin sample was supported by the MRC and Mercer's Institute for Research on Ageing. The LASER-AD study was funded by Lundbeck SA. GR is supported by a program grant from the MRC (G0800509). We also thank Advanced Research Computing @ Cardiff (ARCCA) who facilitated data analysis. NIA-LOAD: Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Samples used in this study were obtained from the National Cell Repository for Alzheimer's Disease (NCRAD). Jennifer Williamson, Susan LaRusse Eckert and Stephanie Doan (Columbia University), Michele Goodman (Indiana University) and Elise Weamer (University of Pittsburgh) helped coordinate the project across the United States. We especially acknowledge the support and guidance of Creighton H Phelps, PhD, at the National Institute on Aging. ADRC: The following investigators and Alzheimer's Disease Centers participated in the Study: Boston University Robert Green, Neil Kowall, Lindsay Farrer; Columbia University Jennifer Williamson, Vincent Santana; Duke University Donald Schmechel, Peter Gaskel; Indiana University, Bernardino Ghetti, Martin R Farlow, Kelly Horner; Massachusetts General Hospital John H Growdon, Deborah Blacker, Rudolph E Tanzi, Bradley T Hyman; Mayo Clinic-Rochester Bradley Boeve, Karen Kuntz, Lindsay Norgaard, Nathan Larson; Mayo Clinic-Jacksonville Dana Kistler, Fracine Parfitt, Jenny Haddow; Mount Sinai School of Medicine Jeremy Silverman, Michal Schnaider Beeri, Mary Sano, Joy Wang, Rachel Lally; Northwestern University Nancy Johnson, Marcel Mesulum, Sandra Weintraub, Eileen Bigio; Oregon Health and Science University Jeffery Kaye, Patricia Kramer, Jessica Payne-Murphy ; Rush University David Bennett, Holli Jacobs, Jeen-Soo Chang, Danielle Arends; University of Alabama at Birmingham Lindy Harrell; University of California, Los Angeles George Bartzokis, Jeffery Cummings, Po H Lu, Usha Toland; University of Kentucky William Markesbery, Charles Smith, Alise Brickhouse; University of Pennsylvania John Trojanowski, Vivianna Van Deerlin, Elisabeth McCarty Wood; University of Pittsburgh Oscar L Lopez, Robert A Sweet; University of Southern California I Helena Chui, Arousiak Varpetian; University of Texas Southwestern Ramon Diaz-Arrastia, Roger Rosenberg, Barbara Davis; University of Washington Thomas Bird, Malia Rumbaugh, Gerard D Schellenberg, Murray Raskind; Washington University at St Louis Alison Goate, John Morris, Joanne Norton, Denise Levitch, Betsy Grant, Mary Coats. This study was supported by the following federal grants: U24AG026395 (NIA-LOAD Family Study); U24AG021886 (National Cell Repository for Alzheimer's Disease); R01AG027224, R01AG030653 and P50AG005133 University of Pittsburgh; P30AG10161 Rush University Medical Center; P30AG013846 Boston University; P50AG08702 Columbia University; P30AG028377 Duke University; P30AG010133 Indiana University; P50AG05134 Massachusetts General Hospital; P50AG165574 Mayo Clinic, Rochester and Mayo Clinic, Jacksonville; P01AG05138, P01AG02219, and P50AG05138 Mount Sinai School of Medicine; P30AG13854 Northwestern University Medical School; P30AG008017 Oregon Health and Science University; P50AG016582 University of Alabama at Birmingham; P50AG016579 David Geffen School of Medicine, University of California, Los Angeles; P30AG028383 University of Kentucky, Lexington; P30AG10124 University of Pennsylvania; P50AG05142 University of Southern California; P30AG12300 The University of Texas Southwestern Medical Center; P50AG05136 University of Washington; and P50AG05681 and P01AG03991 Washington University School of Medicine. Collection and ascertainment of the ADRC subjects was supported by USPHS grants AG027224. We thank contributors who collected samples used in this study, and we particularly thank the patients and their families, whose help and participation made this work possible.

Author information

Author notes

  1. P Hollingworth, R Sweet and R Sims: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK

    P Hollingworth, R Sims, D Harold, G Russo, R Abraham, A Stretton, N Jones, A Gerrish, J Chapman, D Ivanov, V Moskvina, P Holmans, L Jones, M J Owen, M C O'Donovan & J Williams

  2. Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

    R Sweet, B Devlin & L Klei

  3. Department of Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

    R Sweet, S T DeKosky & O L Lopez

  4. VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA, USA

    R Sweet

  5. Department of Neuroscience, Kings College London, Institute of Psychiatry, London, UK

    S Lovestone, P Priotsi & M Lupton

  6. Institute of Public Health, University of Cambridge, Cambridge, UK

    C Brayne

  7. Mercer's Institute for Research on Aging, St James Hospital and Trinity College, Dublin, Ireland

    M Gill, B Lawlor & A Lynch

  8. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University of Belfast, Belfast, UK

    D Craig, B McGuinness, J Johnston & P Passmore

  9. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK

    C Holmes

  10. Department of Mental Health Sciences, University College London, London, UK

    G Livingston, N J Bass, H Gurling & A McQuillin

  11. Taub Institute and the Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY, USA

    M M Barmada & R Mayeux

  12. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    F Y Demirci & M I Kamboh

  13. University of Virginia School of Medicine, Charlottesville, VA, USA

    S T DeKosky

Authors
  1. P Hollingworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Sweet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Sims
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Harold
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Stretton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Gerrish
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Ivanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. V Moskvina
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Lovestone
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P Priotsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Lupton
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. C Brayne
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. B Lawlor
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. A Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. D Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. B McGuinness
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. J Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. C Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. G Livingston
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. N J Bass
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. H Gurling
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. A McQuillin
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. P Holmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. L Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. B Devlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. L Klei
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. M M Barmada
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. F Y Demirci
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. S T DeKosky
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. O L Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. P Passmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. M J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. M C O'Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. R Mayeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. M I Kamboh
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. J Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the GERAD Consortium

the National Institute on Aging Late-Onset Alzheimer's Disease Family Study Group

Corresponding authors

Correspondence to R Sweet or J Williams.

Ethics declarations

Competing interests

Professor Williams and Dr Harold have a patent application with respect to genes identified in the GWAS of Harold et al.:2 this study provided data for this manuscript and was funded by the MRC and the Wellcome Trust.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

PowerPoint slides

Supplementary information

Appendices

Appendix A

Data used in the preparation of this article were obtained from the Genetic and Environmental Risk in Alzheimer's disease GWAS (GERAD) genome-wide association study (Harold et al.2). Hence, the investigators within the GERAD consortium contributed to the design and implementation of GERAD and/or provided data but did not participate in the analysis or writing of this report. See Supplementary Content for members of the GERAD consortium.

Appendix B

Data used in the preparation of this article were obtained from the National Institute on Aging Late-Onset Alzheimer’s disease Family Study Group (NIA-LOAD). Hence, the investigators within the NIA-LOAD consortium contributed to the design and implementation of NIA-LOAD and/or provided data but did not participate in the analysis or writing of this report. See Supplementary Content for members of the NIA-LOAD consortium.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hollingworth, P., Sweet, R., Sims, R. et al. Genome-wide association study of Alzheimer's disease with psychotic symptoms. Mol Psychiatry 17, 1316–1327 (2012). https://doi.org/10.1038/mp.2011.125

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2011.125

Keywords

This article is cited by

Search

Advanced search

Quick links