Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders DOI Creative Commons
Lachlan Gilchrist, Julian Mutz, Pirro G. Hysi

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Abstract Evidence indicates phenotypic and biological overlap between psychiatric neurodegenerative disorders. Further identification of underlying mutual unique mechanisms may yield novel multi-disorder disorder-specific therapeutic targets. The metabolome represents an important domain for target as metabolites play critical roles in modulating a diverse range processes. Here, we used Mendelian randomisation (MR) to test the causal effects ∼1000 plasma ∼300 metabolite ratios on anxiety, bipolar disorder, depression, schizophrenia, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease multiple sclerosis. In total, 85 involving 77 passed FDR correction robust sensitivity analyses (IVW-MR OR range: 0.73-1.48; p < 0.05). No evidence reverse causality was identified. Multivariate implicated sphingolipid metabolism disorder risk carnitine derivatives sclerosis However, polygenic scores prioritised showed limited prediction UK Biobank. Downstream colocalisation regions containing influential variants identified greater than suggestive (PP.H4 ≥ 0.6) shared variant 29 metabolite/psychiatric trait-pairs chromosome 11 at FADS gene cluster. Most these were lipids linoleic or arachidonic acid. Additional ratio histidine-to-glutamine, glutamine, SPRYD4 expression 12. Although no single had effect results suggest broad across brain Metabolites here help inform future targeted interventions.

Language: Английский

Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders DOI Creative Commons
Lachlan Gilchrist, Julian Mutz, Pirro G. Hysi

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Abstract Evidence indicates phenotypic and biological overlap between psychiatric neurodegenerative disorders. Further identification of underlying mutual unique mechanisms may yield novel multi-disorder disorder-specific therapeutic targets. The metabolome represents an important domain for target as metabolites play critical roles in modulating a diverse range processes. Here, we used Mendelian randomisation (MR) to test the causal effects ∼1000 plasma ∼300 metabolite ratios on anxiety, bipolar disorder, depression, schizophrenia, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease multiple sclerosis. In total, 85 involving 77 passed FDR correction robust sensitivity analyses (IVW-MR OR range: 0.73-1.48; p < 0.05). No evidence reverse causality was identified. Multivariate implicated sphingolipid metabolism disorder risk carnitine derivatives sclerosis However, polygenic scores prioritised showed limited prediction UK Biobank. Downstream colocalisation regions containing influential variants identified greater than suggestive (PP.H4 ≥ 0.6) shared variant 29 metabolite/psychiatric trait-pairs chromosome 11 at FADS gene cluster. Most these were lipids linoleic or arachidonic acid. Additional ratio histidine-to-glutamine, glutamine, SPRYD4 expression 12. Although no single had effect results suggest broad across brain Metabolites here help inform future targeted interventions.

Language: Английский

Citations

0