Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities

N.E. Steen, Z. Rahman, A. Szabo, G.F.L. Hindley, N. Parker, W. Cheng, A. Lin, K.S. O'Connell, M.A. Sheikh, A. Shadrin, S. Bahrami, S. Karthikeyan, E.Z. Hoseth, A.M. Dale, P. Aukrust, O.B. Smeland, T. Ueland, O. Frei, S. Djurovic, O.A. Andreassen

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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 (rg = 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.

Original languageEnglish
Pages (from-to)1345-1354
Number of pages10
JournalSchizophrenia Bulletin
Issue number5
Early online date15 Jun 2023
Publication statusPublished - 1 Sept 2023

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