Multiomic approach and Mendelian randomization analysis identify causal associations between blood biomarkers and subcortical brain structure volumes

• Published in: NeuroImage (Orlando, Fla.) Vol. 284; p. 120466
• Main Authors: Jain, Pritesh R, Yates, Madison, de Celis, Carlos Rubin, Drineas, Petros, Jahanshad, Neda, Thompson, Paul, Paschou, Peristera
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2023; Elsevier Limited; Elsevier
• Subjects: Alzheimer's disease; Amygdala; Anorexia; Apoptosis; Autism; Biomarkers; Brain - diagnostic imaging; Brain - pathology; Complement component C1; Datasets; Disease; Endoplasmic reticulum; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Globus pallidus; Humans; Magnetic Resonance Imaging - methods; Mendelian randomization; Mendelian Randomization Analysis; Mental disorders; Metabolism; Metabolites; Microbiota; Multiomics; Neurodevelopmental disorders; Neurological disorders; Nucleus accumbens; Plasma proteins; Post traumatic stress disorder; Proteinase inhibitors; Proteins; Proteolysis; Proteome; Putamen; Schizophrenia; Signal transduction; Subcortical brain volume; Thalamus; Uric acid; Proteome; Mendelian randomization; Metabolites; Neurological disorders; Subcortical brain volume
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2023.120466

•A two sample Mendelian randomization approach was used to identify proteins, metabolites, or microbes that have a putative causal association with subcortical brain structure volumes.•Eleven proteins and six metabolites were found to have a significant association with subcortical structure volumes, with nine proteins and five metabolites being replicated using independent exposure data.•Heterogeneity and pleiotropy analysis showed low to no deviation from null thus validating our associations as truly significant.•The study highlighted the role of proteolytic and anti-oxidative components in the development and functioning of the brain.•The results provide novel insight for understanding subcortical brain structure changes and could help in uncovering potential diagnostic markers and drug targets for the many disorders that are associated with changes in brain structures. Alterations in subcortical brain structure volumes have been found to be associated with several neurodegenerative and psychiatric disorders. At the same time, genome-wide association studies (GWAS) have identified numerous common variants associated with brain structure. In this study, we integrate these findings, aiming to identify proteins, metabolites, or microbes that have a putative causal association with subcortical brain structure volumes via a two-sample Mendelian randomization approach. This method uses genetic variants as instrument variables to identify potentially causal associations between an exposure and an outcome. The exposure data that we analyzed comprised genetic associations for 2994 plasma proteins, 237 metabolites, and 103 microbial genera. The outcome data included GWAS data for seven subcortical brain structure volumes including accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Eleven proteins and six metabolites were found to have a significant association with subcortical structure volumes, with nine proteins and five metabolites replicated using independent exposure data. We found causal associations between accumbens volume and plasma protease c1 inhibitor as well as strong association between putamen volume and Agouti signaling protein. Among metabolites, urate had the strongest association with thalamic volume. No significant associations were detected between the microbial genera and subcortical brain structure volumes. We also observed significant enrichment for biological processes such as proteolysis, regulation of the endoplasmic reticulum apoptotic signaling pathway, and negative regulation of DNA binding. Our findings provide insights to the mechanisms through which brain volumes may be affected in the pathogenesis of neurodevelopmental and psychiatric disorders and point to potential treatment targets for disorders that are associated with subcortical brain structure volumes.