Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

Elleke Tissink; Siemon C. de Lange; Jeanne E. Savage; Douglas P. Wightman; Christiaan A. de Leeuw; Kristen M. Kelly; Mats Nagel; Martijn P. van den Heuvel; Danielle Posthuma

doi:10.1038/s42003-022-03672-7

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

Elleke Tissink, Siemon C. de Lange, Jeanne E. Savage, Douglas P. Wightman, Christiaan A. de Leeuw, Kristen M. Kelly, Mats Nagel, Martijn P. van den Heuvel, Danielle Posthuma^*

^*Corresponding author for this work

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

Abstract

Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations study for cerebellar volume was performed in a discovery sample of 27,486 individuals from UK Biobank, resulting in 30 genome-wide significant loci and a SNP heritability of 39.82%. We pinpoint the likely causal variants and those that have effects on amino acid sequence or cerebellar gene-expression. Additionally, 85 genome-wide significant genes were detected and tested for convergence onto biological pathways, cerebellar cell types, human evolutionary genes or developmental stages. Local genetic correlations between cerebellar volume and neurodevelopmental and neurodegenerative disorders reveal shared loci with Parkinson's disease, Alzheimer's disease and schizophrenia. These results provide insights into the heritable mechanisms that contribute to developing a brain structure important for cognitive functioning and mental health.

Original language	English
Article number	710
Pages (from-to)	1-12
Number of pages	12
Journal	Communications biology
Volume	5
DOIs	https://doi.org/10.1038/s42003-022-03672-7
Publication status	Published - 16 Jul 2022

Bibliographical note

Funding Information:
D.P. was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). The work of S.L. was supported by ZonMw Open Competition, project REMOVE 09120011910032. D.W. was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012). C.L. is funded by Hoffman-La Roche. The work of M.H. was supported by a VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and an ERC Consolidator of the European Research Council (101001062). The research has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. We thank J.P. Beauchamp for his clarifying emails about the holistic replication method.

Funding Information:
D.P. was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). The work of S.L. was supported by ZonMw Open Competition, project REMOVE 09120011910032. D.W. was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012). C.L. is funded by Hoffman-La Roche. The work of M.H. was supported by a VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and an ERC Consolidator of the European Research Council (101001062). The research has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. We thank J.P. Beauchamp for his clarifying emails about the holistic replication method.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Brain
Genome-Wide Association Study/methods
Humans
Mental Health
Polymorphism, Single Nucleotide
Schizophrenia/genetics

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Tissink, E., de Lange, S. C., Savage, J. E., Wightman, D. P., de Leeuw, C. A., Kelly, K. M., Nagel, M., van den Heuvel, M. P., & Posthuma, D. (2022). Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health. Communications biology, 5, 1-12. Article 710. https://doi.org/10.1038/s42003-022-03672-7

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title = "Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health",

abstract = "Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations study for cerebellar volume was performed in a discovery sample of 27,486 individuals from UK Biobank, resulting in 30 genome-wide significant loci and a SNP heritability of 39.82%. We pinpoint the likely causal variants and those that have effects on amino acid sequence or cerebellar gene-expression. Additionally, 85 genome-wide significant genes were detected and tested for convergence onto biological pathways, cerebellar cell types, human evolutionary genes or developmental stages. Local genetic correlations between cerebellar volume and neurodevelopmental and neurodegenerative disorders reveal shared loci with Parkinson's disease, Alzheimer's disease and schizophrenia. These results provide insights into the heritable mechanisms that contribute to developing a brain structure important for cognitive functioning and mental health.",

keywords = "Brain, Genome-Wide Association Study/methods, Humans, Mental Health, Polymorphism, Single Nucleotide, Schizophrenia/genetics",

author = "Elleke Tissink and {de Lange}, {Siemon C.} and Savage, {Jeanne E.} and Wightman, {Douglas P.} and {de Leeuw}, {Christiaan A.} and Kelly, {Kristen M.} and Mats Nagel and {van den Heuvel}, {Martijn P.} and Danielle Posthuma",

note = "Funding Information: D.P. was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). The work of S.L. was supported by ZonMw Open Competition, project REMOVE 09120011910032. D.W. was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012). C.L. is funded by Hoffman-La Roche. The work of M.H. was supported by a VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and an ERC Consolidator of the European Research Council (101001062). The research has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. We thank J.P. Beauchamp for his clarifying emails about the holistic replication method. Funding Information: D.P. was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). The work of S.L. was supported by ZonMw Open Competition, project REMOVE 09120011910032. D.W. was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012). C.L. is funded by Hoffman-La Roche. The work of M.H. was supported by a VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and an ERC Consolidator of the European Research Council (101001062). The research has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. We thank J.P. Beauchamp for his clarifying emails about the holistic replication method. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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N2 - Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations study for cerebellar volume was performed in a discovery sample of 27,486 individuals from UK Biobank, resulting in 30 genome-wide significant loci and a SNP heritability of 39.82%. We pinpoint the likely causal variants and those that have effects on amino acid sequence or cerebellar gene-expression. Additionally, 85 genome-wide significant genes were detected and tested for convergence onto biological pathways, cerebellar cell types, human evolutionary genes or developmental stages. Local genetic correlations between cerebellar volume and neurodevelopmental and neurodegenerative disorders reveal shared loci with Parkinson's disease, Alzheimer's disease and schizophrenia. These results provide insights into the heritable mechanisms that contribute to developing a brain structure important for cognitive functioning and mental health.

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Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

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