Novel genomic risk loci and improved prediction for treatment-resistant schizophrenia are revealed by leveraging polygenic overlap with body-mass index

Author:

O'Connell Kevin1ORCID,Koch Elise1,Lenk Hasan,Akkouh Ibrahim,Hindley Guy2ORCID,Jaholkowski Piotr,Smith Robert3ORCID,Holen Børge,Shadrin Alexey,Frei Oleksandr2,Smeland OlavORCID,Steen Nils Eiel2ORCID,Dale Anders4ORCID,Molden Espen3ORCID,Djurovic Srdjan5ORCID,Andreassen Ole6ORCID

Affiliation:

1. NORMENT, University of Oslo

2. University of Oslo

3. Diakonhjemmet hospital

4. University of California, San Diego

5. Oslo University Hospital

6. Oslo University Hospital & Institute of Clinical Medicine, University of Oslo

Abstract

Abstract Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR < 0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

Publisher

Research Square Platform LLC

Reference50 articles.

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5. Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia;Pardinas AF;JAMA psychiatry,2022

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