Abstract
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.
Competing Interest Statement
Dr. Andreassen has received speaker's honorarium from Lundbeck, and is a consultant to HealthLytix. Dr. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The other authors declare no competing interests.
Footnotes
Refined loci selection and the corresponding relevancy to biological pathways. The focus of the results was shift to make it clear why modeling tissue compositions matters.