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  • Original Article
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Genetic risk for schizophrenia and psychosis in Alzheimer disease

Molecular Psychiatry volume 23, pages 963–972 (2018)Cite this article

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A Correction to this article was published on 12 March 2019

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Abstract

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

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References

  1. 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 

  2. 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 

  3. Emanuel JE, Lopez OL, Houck PR, Becker JT, Weamer EA, DeMichele-Sweet MA et al. Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. Am J Geriatr Psychiatry 2011; 19: 160–168.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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: 1155–1162.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Seltman HJ, Mitchell S, Sweet RA . A Bayesian model of psychosis symptom trajectory in Alzheimer's disease. Int J Geriatr Psychiatry 2016; 31: 204–210.

    Article  PubMed  Google Scholar 

  6. Sweet RA, Seltman H, Emanuel JE, Lopez OL, Becker JT, Bis JC et al. Effect of Alzheimer's disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study. Am J Psychiatry 2012; 169: 954–962.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Koppel J, Sunday S, Goldberg TE, Davies P, Christen E, Greenwald BS . Psychosis in Alzheimer's disease is associated with frontal metabolic impairment and accelerated decline in working memory: findings from the Alzheimer's Disease Neuroimaging Initiative. Am J Geriatr Psychiatry 2014; 22: 698–707.

    Article  PubMed  Google Scholar 

  8. Koppel J, Goldberg TE, Gordon ML, Huey E, Davies P, Keehlisen L et al. Relationships between behavioral syndromes and cognitive domains in Alzheimer disease: the impact of mood and psychosis. Am J Geriatr Psychiatry 2012; 20: 994–1000.

    Article  PubMed  Google Scholar 

  9. Gilley DW, Whalen ME, Wilson RS, Bennett DA . Hallucinations and associated factors in Alzheimer's disease. J Neuropsychiatry 1991; 3: 371–376.

    Article  CAS  Google Scholar 

  10. Gilley DW, Wilson RS, Beckett LA, Evans DA . Psychotic symptoms and physically aggressive behavior in Alzheimer's disease. J Am Geriatr Soc 1997; 45: 1074–1079.

    Article  CAS  PubMed  Google Scholar 

  11. Sweet RA, Pollock BG, Sukonick DL, Mulsant BH, Rosen J, Klunk WE et al. The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer's disease. Int Psychogeriatr 2001; 13: 401–409.

    Article  CAS  PubMed  Google Scholar 

  12. Kaufer DI, Cummings JL, Christine D, Bray T, Castellon S, Masterman D et al. Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease: the Neuropsychiatric Inventory Caregiver Distress Scale. J Am Geriatr Soc 1998; 46: 210–215.

    Article  CAS  PubMed  Google Scholar 

  13. Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol 2005; 62: 1601–1608.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rabins PV, Mace NL, Lucas MJ . The impact of dementia on the family. JAMA 1982; 248: 333–335.

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Magni E, Binetti G, Bianchetti A, Trabucchi M . Risk of mortality and institutionalization in demented patients with delusions. J Geriatr Psychiatry Neurol 1996; 9: 123–126.

    Article  CAS  PubMed  Google Scholar 

  17. Cummings JL, Diaz C, Levy M, Binetti G, Litvan II . Neuropsychiatric syndromes in neurodegenerative disease: frequency and signficance. Semin Clin Neuropsychiatry 1996; 1: 241–247.

    CAS  PubMed  Google Scholar 

  18. Bassiony MM, Steinberg M, Rosenblatt A, Baker A, Lyketsos CG . Delusions and hallucinations in Alzheimer's disease: prevalence and clinical correlates. Int J Geriatr Psychiatry 2000; 15: 99–107.

    Article  CAS  PubMed  Google Scholar 

  19. Wilson RS, Tang Y, Aggarwal NT, Gilley DW, Mccann JJ, Bienias JL et al. Hallucinations, cognitive decline, and death in Alzheimer's disease. Neuroepidemiology 2006; 26: 68–75.

    Article  CAS  PubMed  Google Scholar 

  20. Schneider LS, Dagerman K, Insel PS . Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlledtrials. Am J Geriatr Psychiatry 2006; 14: 191–210.

    Article  PubMed  Google Scholar 

  21. Huybrechts KF, Gerhard T, Crystal S, Olfson M, Avorn J, Levin R et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ 2012; 344: e977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pollock BG, Mulsant BH, Rosen J, Sweet RA, Mazumdar S, Bharucha A et al. A randomized, double-blind, placebo-controlled comparison of citalopram and perphenazine for the acute treatment of psychosis and behavioral disturbances associated with dementia. Am J Psychiatry 2002; 159: 460–465.

    Article  PubMed  Google Scholar 

  23. Leonpacher AK, Peters ME, Drye LT, Makino KM, Newell JA, Devanand DP et al. Effects of citalopram on neuropsychiatric symptoms in Alzheimer's dementia: evidence from the CitAD study. Am J Psychiatry 2016; 173: 473–480.

    Article  PubMed  Google Scholar 

  24. Kales HC, Valenstein M, Kim HM, McCarthy JF, Ganoczy D, Cunningham F et al. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry 2007; 164: 1568–1576.

    Article  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. 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 

  28. Barral S, Vardarajan BN, Reyes-Dumeyer D, Faber KM, Bird TD, Tsuang D et al. Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer's disease families. Neurobiol Aging 2015; 36: 3116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Hollingworth P, Sweet R, Sims R, Harold D, Russo G, Abraham R et al. Genome-wide association study of Alzheimer's disease with psychotic symptoms. Mol Psychiatry 2012; 17: 1316–1327.

    Article  CAS  PubMed  Google Scholar 

  30. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.

    Article  PubMed Central  CAS  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.

    Article  CAS  Google Scholar 

  33. Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G et al. Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Genet 2012; 21: 4781–4792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Los CG, Vazquez AI, Fernando R, Klimentidis YC, Sorensen D . Prediction of complex human traits using the genomic best linear unbiased predictor. PLoS Genet 2013; 9: e1003608.

    Article  CAS  Google Scholar 

  35. Vazquez AI, Klimentidis YC, Dhurandhar EJ, Veturi YC, Paerez-Rodriguez P . Assessment of whole-genome regression for type II diabetes. PLoS ONE 2015; 10: e0123818.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 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 

  37. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al. Theconsortium 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 

  38. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65: 1863–1872.

    Article  CAS  PubMed  Google Scholar 

  39. DeMichele-Sweet MA, Klei L, Devlin B, Ferrell RE, Weamer EA, Emanuel JE et al. No association of psychosis in Alzheimer disease with neurodegenerative pathway genes. Neurobiol Aging 2011; 32: 555–11.

    Article  CAS  PubMed  Google Scholar 

  40. Weamer EA, DeMichele-Sweet MA, Cloonan YK, Lopez OL, Sweet RA . Incident psychosis in subjects with mild cognitive impairment or Alzheimer's disease. J Clin Psychiatry 2016; 77: e1564–e1569.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452–1458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lambert MJ, Hatch DR, Kingston MD, Edwards BC . Zung, Beck, and Hamilton Rating Scales as measures of treatment outcome: a meta-analytic comparison. J Consult Clin Psychol 1986; 54: 54–59.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

  45. 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. Am J Psychiatry 1995; 152: 1349–1357.

    Article  CAS  PubMed  Google Scholar 

  46. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 2000; 12: 233–239.

    Article  CAS  PubMed  Google Scholar 

  47. Boada M, Cejudo JC, Tarraga L, Lopez OL, Kaufer D . Neuropsychiatric Inventory Questionnaire (NPI-Q): Spanish validation of a brief clinical form of the Neuropsychiatric inventory (NPI). Neurologia 2002; 17: 317–323.

    CAS  PubMed  Google Scholar 

  48. 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 

  49. Overall JE, Gorham DR . The brief psychiatric rating scale. Psychol Rep 1962; 10: 799–812.

    Article  Google Scholar 

  50. Zubenko GS, Rosen J, Sweet RA, Mulsant BH, Rifai AH . Impact of psychiatric hospitalization on behavioral complications of Alzheimer's disease. Am J Psychiatry 1992; 149: 1484–1491.

    Article  CAS  PubMed  Google Scholar 

  51. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL . A new clinical scale for the staging of dementia. Br J Psychiatry 1982; 140: 566–572.

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Bacanu SA, Devlin B, Chowdari KV, DeKosky ST, Nimgaonkar VL, Sweet RA . Linkage analysis of Alzheimer disease with psychosis. Neurology 2002; 59: 118–120.

    Article  CAS  PubMed  Google Scholar 

  54. Affymetrix axiom assay user manual 2010; https://www.affymetrix.com/support/downloads/manuals/axiom_assay_user_manual.pdf.

  55. 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 

  56. SCZ1 Dataset 2016; https://www.med.unc.edu/pgc/results-and-downloads.

  57. Lin CW, Chang LC, Tseng GC, Kirkwood CM, Sibille EL, Sweet RA . VSNL1 co-expression networks in aging include calcium signaling, synaptic plasticity, and Alzheimer's disease pathways. Front Psychiatry 2015; 6: 30.

    PubMed  PubMed Central  Google Scholar 

  58. Seney ML, Chang LC, Oh H, Wang X, Tseng GC, Lewis DA et al. The role of genetic sex in affect regulation and expression of GABA-related genes across species. Front Psychiatry 2013; 4: 104.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kirov G . CNVs in neuropsychiatric disorders. Hum Mol Genet 2015; 24: R45–R49.

    Article  CAS  PubMed  Google Scholar 

  60. Mulle JG, Pulver AE, McGrath JA, Wolyniec PS, Dodd AF, Cutler DJ et al. Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. Biol Psychiatry 2014; 75: 371–377.

    Article  CAS  PubMed  Google Scholar 

  61. Banerjee A, MacDonald ML, Borgmann-Winter KE, Hahn CG . Neuregulin 1-erbB4 pathway in schizophrenia: From genes to an interactome. Brain Res Bull 2010; 83: 132–139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet 2010; 87: 229–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA et al. Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 2001; 105: 20–22.

    Article  CAS  PubMed  Google Scholar 

  64. Chang CC, Chow CC, Tellier LCAM, Vattikuti S, Purcell SM, Lee JJ . Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 2015; 4https://www.cog-genomics.org/plink2.

  65. Kosoy R, Nassir R, Tian C, White PA, Butler LM, Silva G et al. Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Hum Mutat 2009; 30: 69–78.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Klei L, Kent BP, Melhem N, Devlin B, Roeder K . GemTools: A fast and efficient approach to estimating genetic ancestry. arXiv.org (https://arxiv.org/abs/1104.1162, 2011. http://wpicr.wpic.pitt.edu/WPICCompGen/GemTools/GemTools.htm.

  67. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2017. https://www.R-project.org/.

  68. 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 

  69. Murray PS, Kumar S, DeMichele-Sweet MA, Sweet RA . Psychosis in Alzheimer's disease. Biol Psychiatry 2014; 75: 542–552.

    Article  PubMed  Google Scholar 

  70. 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 

  71. Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF . Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative. Arch Neurol 1994; 51: 1198–1204.

    Article  CAS  PubMed  Google Scholar 

  72. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013; 45: 1238–1243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wilkaniec A, Czapski GA, Adamczyk A . Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. J Neurochem 2016; 136: 222–233.

    Article  CAS  PubMed  Google Scholar 

  74. Okamoto K, Beach D . Cyclin G is a transcriptional target of the p53 tumor suppressor protein. EMBO J 1994; 13: 4816–4822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jordan-Sciutto KL, Morgan K, Bowser R . Increased Cyclin G1 immunoreactivity during Alzheimer's disease. J Alzheimers Dis 1999; 1: 409–417.

    Article  CAS  PubMed  Google Scholar 

  76. Kotrla KJ, Chacko RC, Harper RG, Doody R . Clinical variables associated with psychosis in Alzheimer's disease. Am J Psychiatry 1995; 152: 1377–1379.

    Article  CAS  PubMed  Google Scholar 

  77. Smoller JW, Ripke S, Lee SH . Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379.

    Article  CAS  Google Scholar 

  78. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016; 530: 177–183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 2016; 19: 1442–1453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li M, Jaffe AE, Straub RE, Tao R, Shin JH, Wang Y et al. A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus. Nat Med 2016; 22: 649–656.

    Article  CAS  PubMed  Google Scholar 

  81. Gambuzza ME, Sofo V, Salmeri FM, Soraci L, Marino S, Bramanti P . Toll-like receptors in Alzheimer's disease: a therapeutic perspective. CNS Neurol Disord Drug Targets 2014; 13: 1542–1558.

    Article  CAS  PubMed  Google Scholar 

  82. Mani M, Lee UH, Yoon NA, Kim HJ, Ko MS, Seol W et al. Developmentally regulated GTP-binding protein 2 coordinates Rab5 activity and transferrin recycling. Mol Biol Cell 2016; 27: 334–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M . Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol 2003; 161: 609–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Brown TC, Tran IC, Backos DS, Esteban JA . NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 2005; 45: 81–94.

    Article  CAS  PubMed  Google Scholar 

  85. Tumbarello DA, Waxse BJ, Arden SD, Bright NA, Kendrick-Jones J, Buss F . Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome. Nat Cell Biol 2012; 14: 1024–1035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li L, Zhang X, Le W . Autophagy dysfunction in Alzheimer's disease. Neurodegener Dis 2010; 7: 265–271.

    PubMed  Google Scholar 

  87. Merenlender-Wagner A, Malishkevich A, Shemer Z, Udawela M, Gibbons A, Scarr E et al. Autophagy has a key role in the pathophysiology of schizophrenia. Mol Psychiatry 2015; 20: 126–132.

    Article  CAS  PubMed  Google Scholar 

  88. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT . Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 2007; 27: 135–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Eckart N, Song Q, Yang R, Wang R, Zhu H, McCallion AS et al. Functional characterization of schizophrenia-associated variation in CACNA1C. PLoS ONE 2016; 11: e0157086.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Andrade A, Hope J, Allen A, Yorgan V, Lipscombe D, Pan JQ . A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity. Sci Rep 2016; 6: 34233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Macdonald ML, Alhassan J, Newman JT, Richard M, Gu H, Kelley RM et al. Selective loss of smaller spines in schizophrenia. Am J Psychiatry 2017 (in press).

  93. Briggs CA, Chakroborty S, Stutzmann GE . Emerging pathways driving early synaptic pathology in Alzheimer's disease. Biochem Biophys Res Commun 2017; 483: 988–997.

    Article  CAS  PubMed  Google Scholar 

  94. Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J et al. Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future. Alzheimers Dement 2013; 9: 602–608.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Corvin A, Craddock N, Sullivan PF . Genome-wide association studies: a primer. Psychol Med 2010; 40: 1063–1077.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the following federal grants: AG027224 (to RAS), AG005133 (to RAS), BX000452 (to RAS), MH057881 (to BD), AG030653 (to MIK), AG041718 (to MIK) and MH093723 (to ELS). This project used the University of Pittsburgh HSCRF Genomics Research Core iPlex and Specimen Processing services. Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC) and/or Alzheimer’s Research UK (ARUK) and the Welsh Assembly Government (to RS and JW).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Department of Veterans Affairs or the US Government.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    M A A DeMichele-Sweet, L Klei, O L Lopez, E L Sibille, B Devlin & R A Sweet

  2. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    E A Weamer, O L Lopez & R A Sweet

  3. Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA

    D T Vrana

  4. Genomics Research Core of the Health Sciences Core Research Facilities, University of Pittsburgh, Pittsburgh, PA, USA

    D J Hollingshead

  5. Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA

    H J Seltman

  6. Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK

    R Sims & J Williams

  7. Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    T Foroud

  8. Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain

    I Hernandez, S Moreno-Grau, L Tárraga, M Boada & A Ruiz

  9. Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA

    R Mayeux

  10. Department of Psychiatry and Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    E L Sibille

  11. Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada

    E L Sibille

  12. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    M I Kamboh

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

    R A Sweet

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Correspondence to R A Sweet.

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DeMichele-Sweet, M., Weamer, E., Klei, L. et al. Genetic risk for schizophrenia and psychosis in Alzheimer disease. Mol Psychiatry 23, 963–972 (2018). https://doi.org/10.1038/mp.2017.81

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