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Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities
BACKGROUND: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483470/ https://www.ncbi.nlm.nih.gov/pubmed/37319439 http://dx.doi.org/10.1093/schbul/sbad082 |
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author | Steen, Nils Eiel Rahman, Zillur Szabo, Attila Hindley, Guy F L Parker, Nadine Cheng, Weiqiu Lin, Aihua O’Connell, Kevin S Sheikh, Mashhood A Shadrin, Alexey Bahrami, Shahram Karthikeyan, Sandeep Hoseth, Eva Z Dale, Anders M Aukrust, Pål Smeland, Olav B Ueland, Thor Frei, Oleksandr Djurovic, Srdjan Andreassen, Ole A |
author_facet | Steen, Nils Eiel Rahman, Zillur Szabo, Attila Hindley, Guy F L Parker, Nadine Cheng, Weiqiu Lin, Aihua O’Connell, Kevin S Sheikh, Mashhood A Shadrin, Alexey Bahrami, Shahram Karthikeyan, Sandeep Hoseth, Eva Z Dale, Anders M Aukrust, Pål Smeland, Olav B Ueland, Thor Frei, Oleksandr Djurovic, Srdjan Andreassen, Ole A |
author_sort | Steen, Nils Eiel |
collection | PubMed |
description | BACKGROUND: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. STUDY DESIGN: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. STUDY RESULTS: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%–59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (r(g) = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. CONCLUSIONS: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment. |
format | Online Article Text |
id | pubmed-10483470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-104834702023-09-08 Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities Steen, Nils Eiel Rahman, Zillur Szabo, Attila Hindley, Guy F L Parker, Nadine Cheng, Weiqiu Lin, Aihua O’Connell, Kevin S Sheikh, Mashhood A Shadrin, Alexey Bahrami, Shahram Karthikeyan, Sandeep Hoseth, Eva Z Dale, Anders M Aukrust, Pål Smeland, Olav B Ueland, Thor Frei, Oleksandr Djurovic, Srdjan Andreassen, Ole A Schizophr Bull Regular Articles BACKGROUND: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. STUDY DESIGN: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. STUDY RESULTS: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%–59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (r(g) = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. CONCLUSIONS: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment. Oxford University Press 2023-06-15 /pmc/articles/PMC10483470/ /pubmed/37319439 http://dx.doi.org/10.1093/schbul/sbad082 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Regular Articles Steen, Nils Eiel Rahman, Zillur Szabo, Attila Hindley, Guy F L Parker, Nadine Cheng, Weiqiu Lin, Aihua O’Connell, Kevin S Sheikh, Mashhood A Shadrin, Alexey Bahrami, Shahram Karthikeyan, Sandeep Hoseth, Eva Z Dale, Anders M Aukrust, Pål Smeland, Olav B Ueland, Thor Frei, Oleksandr Djurovic, Srdjan Andreassen, Ole A Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities |
title | Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities |
title_full | Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities |
title_fullStr | Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities |
title_full_unstemmed | Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities |
title_short | Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities |
title_sort | shared genetic loci between schizophrenia and white blood cell counts suggest genetically determined systemic immune abnormalities |
topic | Regular Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483470/ https://www.ncbi.nlm.nih.gov/pubmed/37319439 http://dx.doi.org/10.1093/schbul/sbad082 |
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