Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study

Log in to MyKarger to check if you already have access to this content.

Buy FullText & PDF Unlimited re-access via MyKarger Unrestricted printing, no saving restrictions for personal use read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Access via DeepDyve Unlimited fulltext viewing of this article Organize, annotate And mark up articles Printing And downloading restrictions apply

Select

Subscribe Access to all articles of the subscribed year(s) guaranteed for 5 years Unlimited re-access via Subscriber Login or MyKarger Unrestricted printing, no saving restrictions for personal use read more

Subcription rates

Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview

Abstract of Research Article

Received: August 09, 2022
Accepted: November 21, 2022
Published online: January 09, 2023

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: https://www.karger.com/NPS

Abstract

Introduction: Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. Methods: Genome-wide association study (GWAS) summary data of European participants (n = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. Results: LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230–0.702; p < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], p = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and genus Barnesiella levels were causally associated with TRS but not consistent across MR approaches. Conclusion: This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that genus Barnesiella was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.

© 2023 S. Karger AG, Basel

References McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67–76. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016 Jul 2;388(10039):86–97. Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017 Mar 1;174(3):216–29. Pardiñas AF, Smart SE, Willcocks IR, Holmans PA, Dennison CA, Lynham AJ, et al. Interaction testing and polygenic risk scoring to estimate the association of common genetic variants with treatment resistance in schizophrenia. JAMA Psychiatry. 2022 Mar 1;79(3):260–9. Iasevoli F, Giordano S, Balletta R, Latte G, Formato MV, Prinzivalli E, et al. Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Feb 4;65:34–48. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009 Jan 21;2009(1):Cd000059. Nielsen J, Young C, Ifteni P, Kishimoto T, Xiang YT, Schulte PFJ, et al. Worldwide differences in regulations of clozapine use. CNS Drugs. 2016 Feb;30(2):149–61. Atkin K, Kendall F, Gould D, Freeman H, Liberman J, O'Sullivan D. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry. 1996 Oct;169(4):483–8. Nucifora FC Jr, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2019 Nov;131:104257. Joober R, Rouleau GA, Lal S, Bloom D, Lalonde P, Labelle A, et al. Increased prevalence of schizophrenia spectrum disorders in relatives of neuroleptic-nonresponsive schizophrenic patients. Schizophr Res. 2005 Sep 1;77(1):35–41. Kowalec K, Lu Y, Sariaslan A, Song J, Ploner A, Dalman C, et al. Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study. Mol Psychiatry. 2021 Aug;26(8):4487–95. Gillespie AL, Samanaite R, Mill J, Egerton A, MacCabe JH. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC Psychiatry. 2017 Jan 13;17(1):12. Cross-Disorder Group of the Psychiatric Genomics Consortium Electronic address plee0@mghharvardedu; Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell. 2019;179(7):1469–82.e11. Fanelli G, Franke B, De Witte W, Ruisch IH, Haavik J, van Gils V, et al. Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders. Transl Psychiatry. 2022;12(1):59. Wimberley T, Horsdal HT, Brikell I, Laursen TM, Astrup A, Fanelli G, et al. Temporally ordered associations between type 2 diabetes and brain disorders: a Danish register-based cohort study. BMC Psychiatry. 2022;22(1):573. Shen Y, Xu J, Li Z, Huang Y, Yuan Y, Wang J, et al. Analysis of gut microbiota diversity and auxiliary diagnosis as a biomarker in patients with schizophrenia: a cross-sectional study. Schizophr Res. 2018;197:470–7. Labonté C, Zhand N, Park A, Harvey PD. Complete blood count inflammatory markers in treatment-resistant schizophrenia: evidence of association between treatment responsiveness and levels of inflammation. Psychiatry Res. 2022 Feb;308:114382. Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh PR, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015 Nov;47(11):1236–41. Kappelmann N, Arloth J, Georgakis MK, Czamara D, Rost N, Ligthart S, et al. Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms: a genetic correlation and 2-sample mendelian randomization study. JAMA Psychiatry. 2021;78(2):161–70. Yao Y, Li C, Meng P, Cheng B, Cheng S, Liu L, et al. An atlas of genetic correlations between gestational age and common psychiatric disorders. Autism Res. 2022 Apr 6;15:1008–17. Huang H, Cheng S, Li C, Cheng B, Liu L, Yang X, et al. Dissecting the association between psychiatric disorders and neurological proteins: a genetic correlation and two-sample bidirectional Mendelian Randomization study. Acta Neuropsychiatr. 2022 Mar 28;34(6):311–7. Hartwig FP, Borges MC, Horta BL, Bowden J, Davey Smith G. Inflammatory biomarkers and risk of schizophrenia: a 2-sample mendelian randomization study. JAMA Psychiatry. 2017 Dec 1;74(12):1226–33. Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014 Nov;46(11):1173–86. Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, et al. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet. 2013;45(5):501–12. Wu Y, Murray GK, Byrne EM, Sidorenko J, Visscher PM, Wray NR. GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression. Nat Commun. 2021 Feb 19;12(1):1146. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019 Jan;51(1):63–75. Otowa T, Hek K, Lee M, Byrne EM, Mirza SS, Nivard MG, et al. Meta-analysis of genome-wide association studies of anxiety disorders. Mol Psychiatry. 2016 Oct;21(10):1485–9. Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022 Apr;604(7906):502–8. Kurilshikov A, Medina-Gomez C, Bacigalupe R, Radjabzadeh D, Wang J, Demirkan A, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet. 2021 Feb;53(2):156–65. Choi SW, O’Reilly PF. PRSice-2: polygenic risk score software for biobank-scale data. Gigascience. 2019 Jul 1;8(7):giz082. Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtälä J, Hoti F, Jedenius E, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29,823 patients with schizophrenia. JAMA Psychiatry. 2017 Jul 1;74(7):686–93. 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 Jul 22;44(8):955–9. Delaneau O, Zagury JF, Marchini J. Improved whole-chromosome phasing for disease and population genetic studies. Nat Methods. 2013 Jan;10(1):5–6. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010 Sep 1;26(17):2190–1. Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J; Schizophrenia Working Group of the Psychiatric Genomics Consortium, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015 Mar;47(3):291–5. 1000 Genomes Project Consortium; Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM. A global reference for human genetic variation. Nature. 2015 Oct 1;526(7571):68–74. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018 May 30;7:e34408. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018 Aug 1;27(R2):R195–r208. Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017 Oct;26(5):2333–55. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016 May;40(4):304–14. Greco M FD, Minelli C, Sheehan NA, Thompson JR. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med. 2015 Sep 20;34(21):2926–40. Chi L, Khan I, Lin Z, Zhang J, Lee MYS, Leong W, et al. Fructo-oligosaccharides from Morinda officinalis remodeled gut microbiota and alleviated depression features in a stress rat model. Phytomedicine. 2020 Feb;67:153157. Liu S, Li E, Sun Z, Fu D, Duan G, Jiang M, et al. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci Rep. 2019 Jan 22;9(1):287. Peterson VL, Richards JB, Meyer PJ, Cabrera-Rubio R, Tripi JA, King CP, et al. Sex-dependent associations between addiction-related behaviors and the microbiome in outbred rats. EBioMedicine. 2020 May;55:102769. Samochowiec J, Misiak B. Gut microbiota and microbiome in schizophrenia. Curr Opin Psychiatry. 2021 Sep 1;34(5):503–7. Seeman MV. The gut microbiome and treatment-resistance in schizophrenia. Psychiatr Q. 2020 Mar;91(1):127–36. Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science. 2019 Feb 8;363(6427):eaat9931. Nemani K, Hosseini Ghomi R, McCormick B, Fan X. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jan 2;56:155–60. Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. The microbiota-gut-brain axis. Physiol Rev. 2019 Oct 1;99(4):1877–2013. Flores-Dorantes MT, Díaz-López YE, Gutiérrez-Aguilar R. Environment and gene association with obesity and their impact on neurodegenerative and neurodevelopmental diseases. Front Neurosci. 2020;14:863. Tian Y, Liu D, Wang D, Wang J, Xu H, Dai Q, et al. Obesity in Chinese patients with chronic schizophrenia: prevalence, clinical correlates and relationship with cognitive deficits. Schizophr Res. 2020 Jan;215:270–6. Costa-Dookhan KA, Rajji TK, Tran VN, Bowden S, Mueller DJ, Remington GJ, et al. Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia. Sci Rep. 2021 Jan 21;11(1):2004. Larsen JR, Vedtofte L, Jakobsen MSL, Jespersen HR, Jakobsen MI, Svensson CK, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017 Jul 1;74(7):719–28. Wimberley T, Støvring H, Sørensen HJ, Horsdal HT, MacCabe JH, Gasse C. Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. Lancet Psychiatry. 2016 Apr;3(4):358–66. Donev R, Gantert D, Alawam K, Edworthy A, Hässler F, Meyer-Lindenberg A, et al. Comorbidity of schizophrenia and adult attention-deficit hyperactivity disorder. World J Biol Psychiatry. 2011 Sep;12(Suppl 1):52–6. Arican I, Bass N, Neelam K, Wolfe K, McQuillin A, Giaroli G. Prevalence of attention deficit hyperactivity disorder symptoms in patients with schizophrenia. Acta Psychiatr Scand. 2019 Jan;139(1):89–96. Gudmundsson OO, Walters GB, Ingason A, Johansson S, Zayats T, Athanasiu L, et al. Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder. Transl Psychiatry. 2019 Oct 17;9(1):258. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25. Article / Publication Details

First-Page Preview

Abstract of Research Article

Received: August 09, 2022
Accepted: November 21, 2022
Published online: January 09, 2023

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: https://www.karger.com/NPS

留言 (0)

沒有登入
gif