Bipolar patients display stoichiometric imbalance of gene expression in post-mortem brain samples
© 2024. The Author(s)..
Bipolar disorder is a severe neuro-psychiatric condition where genome-wide association and sequencing studies have pointed to dysregulated gene expression as likely to be causal. We observed strong correlation in expression between GWAS-associated genes and hypothesised that healthy function depends on balance in the relative expression levels of the associated genes and that patients display stoichiometric imbalance. We developed a method for quantifying stoichiometric imbalance and used this to predict each sample's diagnosis probability in four cortical brain RNAseq datasets. The percentage of phenotypic variance on the liability-scale explained by these probabilities ranged from 10.0 to 17.4% (AUC: 69.4-76.4%) which is a multiple of the classification performance achieved using absolute expression levels or GWAS-based polygenic risk scores. Most patients display stoichiometric imbalance in three to ten genes, suggesting that dysregulation of only a small fraction of associated genes can trigger the disorder, with the identity of these genes varying between individuals.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Molecular psychiatry - (2024) vom: 13. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Holmgren, Asbjørn [VerfasserIn] |
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Date Revised 17.02.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1038/s41380-023-02398-0 |
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| funding: |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a Bipolar disorder is a severe neuro-psychiatric condition where genome-wide association and sequencing studies have pointed to dysregulated gene expression as likely to be causal. We observed strong correlation in expression between GWAS-associated genes and hypothesised that healthy function depends on balance in the relative expression levels of the associated genes and that patients display stoichiometric imbalance. We developed a method for quantifying stoichiometric imbalance and used this to predict each sample's diagnosis probability in four cortical brain RNAseq datasets. The percentage of phenotypic variance on the liability-scale explained by these probabilities ranged from 10.0 to 17.4% (AUC: 69.4-76.4%) which is a multiple of the classification performance achieved using absolute expression levels or GWAS-based polygenic risk scores. Most patients display stoichiometric imbalance in three to ten genes, suggesting that dysregulation of only a small fraction of associated genes can trigger the disorder, with the identity of these genes varying between individuals | ||
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| 700 | 1 | |a Bjørnstad, Pål Marius |e verfasserin |4 aut | |
| 700 | 1 | |a Djurovic, Srdjan |e verfasserin |4 aut | |
| 700 | 1 | |a Hughes, Timothy |e verfasserin |4 aut | |
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