Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain

Chun Chieh Fan; Robert Loughnan; Carolina Makowski; Diliana Pecheva; Chi-Hua Chen; Donald J Hagler Jr; Wesley K Thompson; Nadine Parker; Dennis van der Meer; Oleksandr Frei; Ole A Andreassen; Anders M Dale

doi:10.1038/s41467-022-30110-3

Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain

Nat Commun. 2022 May 3;13(1):2423. doi: 10.1038/s41467-022-30110-3.

Authors

Chun Chieh Fan^{1

2

3}, Robert Loughnan⁴, Carolina Makowski^{5

6}, Diliana Pecheva^{5

6}, Chi-Hua Chen⁶, Donald J Hagler Jr^{5

6}, Wesley K Thompson^{7

6}, Nadine Parker⁸, Dennis van der Meer^{8

9}, Oleksandr Frei^{8

10}, Ole A Andreassen⁸, Anders M Dale^{5

6

4

11}

Affiliations

¹ Population Neuroscience and Genetics Lab, University of California, San Diego, La Jolla, CA, USA. [email protected].
² Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA. [email protected].
³ Department of Radiology, School of Medicine, University of California, San Diego, La Jolla, CA, USA. [email protected].
⁴ Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
⁵ Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Radiology, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁷ Population Neuroscience and Genetics Lab, University of California, San Diego, La Jolla, CA, USA.
⁸ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands.
¹⁰ Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
¹¹ Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA.

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 discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adolescent
Benchmarking*
Brain / diagnostic imaging
Brain / metabolism
Cognition
Genetic Loci
Genome-Wide Association Study* / methods
Humans

Abstract

Publication types

MeSH terms

Grants and funding