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.

Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders

Abstract

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E−9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Meta-analysis of ancestry specific genome-wide association studies of composite BACS score.
Fig. 2: Regional plot for the top SNP (rs1076425, P = 3.25 × E−09) and its effect on composite BACS score.

References

  1. 1.

    Hill SK, Reilly JL, Harris MSH, Rosen C, Marvin RW, Deleon O, et al. A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia. Schizophr Res. 2009;113:167–75.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Hill SK, Reilly JL, Keefe RSE, Gold JM, Bishop JR, Gershon ES, et al. Neuropsychological impairments in schizophrenia and psychotic bipolar disorder: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Am J Psychiatry. 2013;170:1275–84.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Hill SK, Beers SR, Kmiec JA, Keshavan MS, Sweeney JA. Impairment of verbal memory and learning in antipsychotic-naïve patients with first-episode schizophrenia. Schizophr Res. 2004;68:127–36.

    PubMed  Article  Google Scholar 

  4. 4.

    Saykin AJ, Shtasel DL, Gur RE, Kester DB, Mozley LH, Stafiniak P, et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51:124–31.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Aas M, Dazzan P, Mondelli V, Melle I, Murray RM, Pariante CM. A systematic review of cognitive function in first-episode psychosis, including a discussion on childhood trauma, stress, and inflammation. Front Psychiatry. 2014;4:182.

    PubMed  Article  Google Scholar 

  6. 6.

    Bilder RM, Goldman RS, Robinson D, Reiter G, Bell L, Bates JA, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry. 2000;157:549–59.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Reilly JL, Sweeney JA. Generalized and specific neurocognitive deficits in psychotic disorders: utility for evaluating pharmacological treatment effects and as intermediate phenotypes for gene discovery. Schizophr Bull. 2014;40:516–22.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Keefe RSE, Fenton WS. How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophr Bull. 2007;33:912–20.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996;153:321–30.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Hill SK, Schuepbach D, Herbener ES, Keshavan MS, Sweeney JA. Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia. Schizophr Res. 2004;68:49–63.

    PubMed  Article  Google Scholar 

  11. 11.

    Stefanopoulou E, Manoharan A, Landau S, Geddes JR, Goodwin G, Frangou S. Cognitive functioning in patients with affective disorders and schizophrenia: a meta-analysis. Int Rev Psychiatry. 2009;21:336–56.

    PubMed  Article  Google Scholar 

  12. 12.

    Velthorst E, Meyer EC, Giuliano AJ, Addington J, Cadenhead KS, Cannon TD, et al. Neurocognitive profiles in the prodrome to psychosis in NAPLS-1. Schizophr Res. 2019;204:311–9.

    PubMed  Article  Google Scholar 

  13. 13.

    Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.

    PubMed  Article  Google Scholar 

  14. 14.

    Smeland OB, Bahrami S, Frei O, Shadrin A, O’Connell K, Savage J, et al. Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. Mol Psychiatry. 2020;25:844–53.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Hubbard L, Tansey KE, Rai D, Jones P, Ripke S, Chambert KD, et al. Evidence of common genetic overlap between schizophrenia and cognition. Schizophr Bull. 2016;42:832–42.

    PubMed  Article  Google Scholar 

  16. 16.

    Hagenaars SP, Harris SE, Davies G, Hill WD, Liewald DCM, Ritchie SJ, et al. Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry. 2016;21:1624–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Trampush JW, Yang MLZ, Yu J, Knowles E, Davies G, Liewald DC, et al. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry. 2017;22:336–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Forstner AJ, Hecker J, Hofmann A, Maaser A, Reinbold CS, Mühleisen TW, et al. Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. PLoS ONE. 2017;12:e0171595.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Yang Z, Zhou D, Li H, Cai X, Liu W, Wang L, et al. The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine. Mol Psychiatry. 2020;25:48–6.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Smeland OB, Frei O, Kauppi K, Hill WD, Li W, Wang Y, et al. Identification of genetic loci jointly influencing schizophrenia risk and the cognitive traits of verbal-numerical reasoning, reaction time, and general cognitive function. JAMA Psychiatry. 2017;74:1065–75.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Harvey PD, Sun N, Bigdeli TB, Fanous AH, Aslan M, Malhotra AK, et al. Genome-wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder. Am J Med Genet B. 2020;183:181–94.

    Article  Google Scholar 

  22. 22.

    Mallet J, Le Strat Y, Dubertret C, Gorwood P. Polygenic risk scores shed light on the relationship between schizophrenia and cognitive functioning: review and meta-analysis. J Clin Med Res. 2020;9:341.

  23. 23.

    Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SOW, Østergaard Christensen T, Leucht S. Second-generation antipsychotic effect on cognition in patients with schizophrenia-a meta-analysis of randomized clinical trials. Acta Psychiatr Scand. 2015;131:185–96.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Sweeney JA, Keilp JG, Haas GL, Hill J, Weiden PJ. Relationships between medication treatments and neuropsychological test performance in schizophrenia. Psychiatry Res. 1991;37:297–308.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Reilly JL, Harris MSH, Keshavan MS, Sweeney JA. Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Arch Gen Psychiatry. 2006;63:1189–97.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005;8:457–72.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Minzenberg MJ, Poole JH, Benton C, Vinogradov S. Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. Am J Psychiatry. 2004;161:116–24.

    PubMed  Article  Google Scholar 

  28. 28.

    Wojtalik JA, Eack SM, Pollock BG, Keshavan MS. Prefrontal gray matter morphology mediates the association between serum anticholinergicity and cognitive functioning in early course schizophrenia. Psychiatry Res. 2012;204:61–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Brébion G, Bressan RA, Amador X, Malaspina D, Gorman JM. Medications and verbal memory impairment in schizophrenia: the role of anticholinergic drugs. Psychol Med. 2004;34:369–74.

    PubMed  Article  Google Scholar 

  30. 30.

    Strauss ME, Reynolds KS, Jayaram G, Tune LE. Effects of anticholinergic medication on memory in schizophrenia. Schizophr Res. 1990;3:127–9.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Keefe RSE, Sweeney JA, Gu H, Hamer RM, Perkins DO, McEvoy JP, et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007;164:1061–71.

    PubMed  Article  Google Scholar 

  32. 32.

    Keedy SK, Reilly JL, Bishop JR, Weiden PJ, Sweeney JA. Impact of antipsychotic treatment on attention and motor learning systems in first-episode schizophrenia. Schizophr Bull. 2015;41:355–65.

    PubMed  Article  Google Scholar 

  33. 33.

    Sweeney JA, Haas GL, Keilp JG, Long M. Evaluation of the stability of neuropsychological functioning after acute episodes of schizophrenia: one-year followup study. Psychiatry Res. 1991;38:63–76.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Chakos MH, Glick ID, Miller AL, Hamner MB, Miller DD, Patel JK, et al. Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial. Psychiatr Serv. 2006;57:1094–101.

    PubMed  Article  Google Scholar 

  35. 35.

    Jeste DV, Gladsjo JA, Lindamer LA, Lacro JP. Medical comorbidity in schizophrenia. Schizophr Bull. 1996;22:413–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharm. 2006;46:1481–6.

    CAS  Article  Google Scholar 

  37. 37.

    Tamminga CA, Ivleva EI, Keshavan MS, Pearlson GD, Clementz BA, Witte B, et al. Clinical phenotypes of psychosis in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Am J Psychiatry. 2013;170:1263–74.

    PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Hill SK, Harris MSH, Herbener ES, Pavuluri M, Sweeney JA. Neurocognitive allied phenotypes for schizophrenia and bipolar disorder. Schizophr Bull. 2008;34:743–59.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Lee J, Rizzo S, Altshuler L, Glahn DC, Miklowitz DJ, Sugar CA, et al. Deconstructing bipolar disorder and schizophrenia: a cross-diagnostic cluster analysis of cognitive phenotypes. J Affect Disord. 2016;209:71–79.

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Harvey PD, Wingo AP, Burdick KE, Baldessarini RJ. Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord. 2010;12:364–75.

    PubMed  Article  Google Scholar 

  41. 41.

    Hill SK, Keshavan MS, Thase ME, Sweeney JA. Neuropsychological dysfunction in antipsychotic-naive first-episode unipolar psychotic depression. Am J Psychiatry. 2004;161:996–1003.

    PubMed  Article  Google Scholar 

  42. 42.

    Herms EN, Bishop JR, Okuneye VT, Tamminga CA, Keshavan MS, Pearlson GD, et al. No connectivity alterations for striatum, default mode, or salience network in association with self-reported antipsychotic medication dose in a large chronic patient group. Schizophr Res. 2020. https://doi.org/10.1016/j.schres.2020.06.017.

  43. 43.

    Eum S, Hill SK, Rubin LH, Carnahan RM, Reilly JL, Ivleva EI, et al. Cognitive burden of anticholinergic medications in psychotic disorders. Schizophr Res. 2017;190:129–35.

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Stevenson JM, Reilly JL, Harris MSH, Patel SR, Weiden PJ, Prasad KM, et al. Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes. Transl Psychiatry. 2016;6:e739.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Keefe RSE, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68:283–97.

    PubMed  Article  Google Scholar 

  46. 46.

    Keefe RSE, Harvey PD, Goldberg TE, Gold JM, Walker TM, Kennel C, et al. Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophr Res. 2008;102:108–15.

    PubMed  Article  Google Scholar 

  47. 47.

    Salahudeen MS, Duffull SB, Nishtala PS. Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC Geriatr. 2015;15:31.

    PubMed  Article  Google Scholar 

  48. 48.

    Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho B-C. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry. 2010;67:255–62.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Alliey-Rodriguez N, Grey TA, Shafee R, Asif H, Lutz O, Bolo NR, et al. NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis. Transl Psychiatry. 2019;9:230.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Sun L, Dimitromanolakis A. PREST-plus identifies pedigree errors and cryptic relatedness in the GAW18 sample using genome-wide SNP data. BMC Proc. 2014;8:S23.

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen W-M. Robust relationship inference in genome-wide association studies. Bioinformatics 2010;26:2867–73.

    CAS  Article  Google Scholar 

  53. 53.

    1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. An integrated map of genetic variation from 1092 human genomes. Nature 2012;491:56–5.

    Article  CAS  Google Scholar 

  54. 54.

    Williams AL, Patterson N, Glessner J, Hakonarson H, Reich D. Phasing of many thousands of genotyped samples. Am J Hum Genet. 2012;91:238–51.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012;44:955–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Lencer R, Mills LJ, Alliey-Rodriguez N, Shafee R, Lee AM, Reilly JL, et al. Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study. Transl Psychiatry. 2017;7:e1249.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Peterson RE, Kuchenbaecker K, Walters RK, Chen C-Y, Popejoy AB, Periyasamy S, et al. Genome-wide association studies in ancestrally diverse populations: opportunities, methods, pitfalls, and recommendations. Cell 2019;179:589–603.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Gershon ES, Pearlson G, Keshavan MS, Tamminga C, Clementz B, Buckley PF, et al. Genetic analysis of deep phenotyping projects in common disorders. Schizophr Res. 2018;195:51–57.

    PubMed  Article  Google Scholar 

  59. 59.

    Clementz BA, Sweeney JA, Hamm JP, Ivleva EI, Ethridge LE, Pearlson GD, et al. Identification of distinct psychosis biotypes using brain-based biomarkers. Am J Psychiatry. 2016;173:373–84.

    PubMed  Article  Google Scholar 

  60. 60.

    Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011;43:977–83.

    Article  CAS  Google Scholar 

  61. 61.

    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421–7.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  62. 62.

    Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA, et al. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry. 2017;7:e993.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Scott LJ, Muglia P, Kong XQ, Guan W, Flickinger M, Upmanyu R, et al. Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry. Proc Natl Acad Sci USA. 2009;106:7501–6.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Chen DT, Jiang X, Akula N, Shugart YY, Wendland JR, Steele CJM, et al. Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatry. 2013;18:195–5.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Li Z, Chen J, Yu H, He L, Xu Y, Zhang D, et al. Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nat Genet. 2017;49:1576–83.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969–76.

    Article  CAS  Google Scholar 

  68. 68.

    Sleiman P, Wang D, Glessner J, Hadley D, Gur RE, Cohen N, et al. GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia/Bipolar susceptibility locus. Sci Rep. 2013;3:3075.

    PubMed  Article  Google Scholar 

  69. 69.

    Li Z, Xiang Y, Chen J, Li Q, Shen J, Liu Y, et al. Loci with genome-wide associations with schizophrenia in the Han Chinese population. Br J Psychiatry. 2015;207:490–4.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, et al. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2018;9:2098.

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–9.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  72. 72.

    Kobayashi H. Endogenous anti-inflammatory substances, inter-alpha-inhibitor and bikunin. Biol Chem. 2006;387:1545–9.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Tsai RYL, McKay RDG. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev. 2002;16:2991–3003.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Song J, Patel M, Rosenzweig CN, Chan-Li Y, Sokoll LJ, Fung ET, et al. Quantification of fragments of human serum inter-alpha-trypsin inhibitor heavy chain 4 by a surface-enhanced laser desorption/ionization-based immunoassay. Clin Chem. 2006;52:1045–53.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Smeland OB, Wang Y, Frei O, Li W, Hibar DP, Franke B, et al. Genetic overlap between schizophrenia and volumes of Hippocampus, putamen, and intracranial volume indicates shared molecular genetic mechanisms. Schizophr Bull. 2017. https://doi.org/10.1093/schbul/sbx148.

  76. 76.

    Vassos E, Steinberg S, Cichon S, Breen G, Sigurdsson E, Andreassen OA, et al. Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder. Biol Psychiatry. 2012;72:645–50.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Kondo K, Ikeda M, Kajio Y, Saito T, Iwayama Y, Aleksic B, et al. Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8) as susceptibility loci for psychotic disorders: a genetic association study. PLoS ONE. 2013;8:e70964.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Lizano P, Lutz O, Xu Y, Rubin LH, Paskowitz L, Lee AM, et al. Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-00914-0.

  79. 79.

    Jeppesen R, Christensen RHB, Pedersen EMJ, Nordentoft M, Hjorthøj C, Köhler-Forsberg O, et al. Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders—a comprehensive systematic review and meta-analysis. Brain Behav Immun. 2020;90:364–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Haam J, Yakel JL. Cholinergic modulation of the hippocampal region and memory function. J Neurochem. 2017;142:111–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Pavuluri MN, West A, Hill SK, Jindal K, Sweeney JA. Neurocognitive function in pediatric bipolar disorder: 3-year follow-up shows cognitive development lagging behind healthy youths. J Am Acad Child Adolesc Psychiatry. 2009;48:299–7.

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families who participated in this study, and Gunvant Thaker, MD, for his scientific contributions to the B-SNIP consortium. We also thank Tom Kono and the University of Minnesota Supercomputing Institute for assistance with DNA array imputation for the replication sample.

Author information

Affiliations

Authors

Contributions

All authors had substantial contributions to either the conceptual design (J.R.B., S.E.), acquisition (J.L.R., S.K.K., E.I., G.D.P., B.A.C., C.A.T., M.S.K., E.S.G., J.A.S., and J.R.B.), analysis (S.E., S.K.H., N.A.R., J.M.S., L.J.M., A.M.L., J.L.R., J.A.S., and J.R.B.), or interpretation of data (all authors) for the work. All authors were involved with drafting the work and/or revising it critically for important intellectual content and approve of the final version to be published. S.E. and J.R.B. agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Jeffrey R. Bishop.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Eum, S., Hill, S.K., Alliey-Rodriguez, N. et al. Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01057-8

Download citation

Search

Quick links