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Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

By Chun Chieh Fan, Robert Loughnan, Diliana Pechva, Chi-Hua Chen, Donald Hagler, Wesley K Thompson, Nadine Parker, Dennis van der Meer, Oleksandr Frei, Ole A. Andreassen, Anders M. Dale

Posted 24 Jun 2021
bioRxiv DOI: 10.1101/2021.06.24.449723

The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. We identified key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development. Our results provide critical implications for potential targets for pharmacological intervention on neuropsychiatric outcomes.

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