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; 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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

How the tissue composition of the human brain is determined remains unclear. Here, the authors apply advanced analyses to two large imaging genetic datasets to identify and validate genetic loci that simultaneously influence multiple brain regions.

Original language	English
Article number	2423
Number of pages	10
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30110-3
Publication status	Published - 3 May 2022

Keywords

Adolescent
Benchmarking
Brain/diagnostic imaging
Cognition
Genetic Loci
Genome-Wide Association Study/methods
Humans
VARIANTS
HIPPOCAMPAL
PHENOTYPES
RESTRICTION
CORTEX
GENES
SCAN
MICROSTRUCTURE

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10.1038/s41467-022-30110-3Licence: CC BY

Cite this

Fan, C. C., Loughnan, R., Makowski, C., Pecheva, D., Chen, C.-H., Hagler, D. J., Thompson, W. K., Parker, N., van der Meer, D., Frei, O., Andreassen, O. A., & Dale, A. M. (2022). Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain. Nature Communications, 13(1), Article 2423. https://doi.org/10.1038/s41467-022-30110-3

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

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.How the tissue composition of the human brain is determined remains unclear. Here, the authors apply advanced analyses to two large imaging genetic datasets to identify and validate genetic loci that simultaneously influence multiple brain regions.",

keywords = "Adolescent, Benchmarking, Brain/diagnostic imaging, Cognition, Genetic Loci, Genome-Wide Association Study/methods, Humans, VARIANTS, HIPPOCAMPAL, PHENOTYPES, RESTRICTION, CORTEX, GENES, SCAN, MICROSTRUCTURE",

author = "Fan, {Chun Chieh} and Robert Loughnan and Carolina Makowski and Diliana Pecheva and Chi-Hua Chen and Hagler, {Donald J} and Thompson, {Wesley K} and Nadine Parker and {van der Meer}, Dennis and Oleksandr Frei and Andreassen, {Ole A} and Dale, {Anders M}",

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year = "2022",

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Fan, CC, Loughnan, R, Makowski, C, Pecheva, D, Chen, C-H, Hagler, DJ, Thompson, WK, Parker, N, van der Meer, D, Frei, O, Andreassen, OA & Dale, AM 2022, 'Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain', Nature Communications, vol. 13, no. 1, 2423. https://doi.org/10.1038/s41467-022-30110-3

TY - JOUR

T1 - Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain

AU - Fan, Chun Chieh

AU - Loughnan, Robert

AU - Makowski, Carolina

AU - Pecheva, Diliana

AU - Chen, Chi-Hua

AU - Hagler, Donald J

AU - Thompson, Wesley K

AU - Parker, Nadine

AU - van der Meer, Dennis

AU - Frei, Oleksandr

AU - Andreassen, Ole A

AU - Dale, Anders M

PY - 2022/5/3

Y1 - 2022/5/3

N2 - 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.How the tissue composition of the human brain is determined remains unclear. Here, the authors apply advanced analyses to two large imaging genetic datasets to identify and validate genetic loci that simultaneously influence multiple brain regions.

AB - 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.How the tissue composition of the human brain is determined remains unclear. Here, the authors apply advanced analyses to two large imaging genetic datasets to identify and validate genetic loci that simultaneously influence multiple brain regions.

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KW - Benchmarking

KW - Brain/diagnostic imaging

KW - Cognition

KW - Genetic Loci

KW - Genome-Wide Association Study/methods

KW - Humans

KW - VARIANTS

KW - HIPPOCAMPAL

KW - PHENOTYPES

KW - RESTRICTION

KW - CORTEX

KW - GENES

KW - SCAN

KW - MICROSTRUCTURE

U2 - 10.1038/s41467-022-30110-3

DO - 10.1038/s41467-022-30110-3

M3 - Article

C2 - 35505052

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2423

ER -