The genetic architecture of human cortical folding

Dennis Van Der Meer; Tobias Kaufmann; Alexey A. Shadrin; Carolina Makowski; Oleksandr Frei; Daniel Roelfs; Jennifer Monereo-Sánchez; David E.J. Linden; Jaroslav Rokicki; Dag Alnæs; Christiaan De Leeuw; Wesley K. Thompson; Robert Loughnan; Chun Chieh Fan; Lars T. Westlye; Ole A. Andreassen; Anders M. Dale

doi:10.1126/sciadv.abj9446

The genetic architecture of human cortical folding

Dennis Van Der Meer, Tobias Kaufmann, Alexey A. Shadrin, Carolina Makowski, Oleksandr Frei, Daniel Roelfs, Jennifer Monereo-Sánchez, David E.J. Linden, Jaroslav Rokicki, Dag Alnæs, Christiaan De Leeuw, Wesley K. Thompson, Robert Loughnan, Chun Chieh Fan, Lars T. Westlye, Ole A. Andreassen, Anders M. Dale

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

Abstract

The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10^-8). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.

Original language	English
Article number	eabj9446
Pages (from-to)	1-9
Number of pages	9
Journal	Science advances
Volume	7
Issue number	51
Early online date	15 Dec 2021
DOIs	https://doi.org/10.1126/sciadv.abj9446
Publication status	Published - 17 Dec 2021

Bibliographical note

Funding Information:
The authors were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795, 298646, and 300767), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, 2017-004, and 2019-101), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC Starting Grant, grant agreement no. 802998), ERA-Net Cofund through the ERA PerMed project "Implement," and the National Institutes of Health (R01MH100351, R01GM104400, U24DA055330, R01MH111359, and U24DA041123; principal investigator: A.M.D.).

Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.

Funding

The authors were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795, 298646, and 300767), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, 2017-004, and 2019-101), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC Starting Grant, grant agreement no. 802998), ERA-Net Cofund through the ERA PerMed project "Implement," and the National Institutes of Health (R01MH100351, R01GM104400, U24DA055330, R01MH111359, and U24DA041123; principal investigator: A.M.D.).

Funders	Funder number
National Institutes of Health	R01GM104400, R01MH111359, U24DA041123, U24DA055330, R01MH100351
National Institutes of Health
Stiftelsen Kristian Gerhard Jebsen	SKGJ-Med-008
Stiftelsen Kristian Gerhard Jebsen
European Research Council
Norges forskningsråd	223273, 229129, 213837, 249795, 300767, 298646, 204966/F20, 248778, 276082, 249795/F20, 225989
Norges forskningsråd
Helse Sør-Øst RHF	2019-101, 2013-123, 2015-073, 2017-004, 2016-064, 2014-097
Helse Sør-Øst RHF
Horizon 2020	802998
Horizon 2020

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Van Der Meer, D., Kaufmann, T., Shadrin, A. A., Makowski, C., Frei, O., Roelfs, D., Monereo-Sánchez, J., Linden, D. E. J., Rokicki, J., Alnæs, D., De Leeuw, C., Thompson, W. K., Loughnan, R., Fan, C. C., Westlye, L. T., Andreassen, O. A., & Dale, A. M. (2021). The genetic architecture of human cortical folding. Science advances, 7(51), 1-9. Article eabj9446. https://doi.org/10.1126/sciadv.abj9446

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title = "The genetic architecture of human cortical folding",

abstract = "The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10-8). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.",

author = "{Van Der Meer}, Dennis and Tobias Kaufmann and Shadrin, {Alexey A.} and Carolina Makowski and Oleksandr Frei and Daniel Roelfs and Jennifer Monereo-S{\'a}nchez and Linden, {David E.J.} and Jaroslav Rokicki and Dag Aln{\ae}s and {De Leeuw}, Christiaan and Thompson, {Wesley K.} and Robert Loughnan and Fan, {Chun Chieh} and Westlye, {Lars T.} and Andreassen, {Ole A.} and Dale, {Anders M.}",

note = "Funding Information: The authors were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795, 298646, and 300767), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, 2017-004, and 2019-101), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC Starting Grant, grant agreement no. 802998), ERA-Net Cofund through the ERA PerMed project {"}Implement,{"} and the National Institutes of Health (R01MH100351, R01GM104400, U24DA055330, R01MH111359, and U24DA041123; principal investigator: A.M.D.). Publisher Copyright: {\textcopyright} 2021 American Association for the Advancement of Science. All rights reserved.",

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month = dec,

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doi = "10.1126/sciadv.abj9446",

language = "English",

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Van Der Meer, D, Kaufmann, T, Shadrin, AA, Makowski, C, Frei, O, Roelfs, D, Monereo-Sánchez, J, Linden, DEJ, Rokicki, J, Alnæs, D, De Leeuw, C, Thompson, WK, Loughnan, R, Fan, CC, Westlye, LT, Andreassen, OA & Dale, AM 2021, 'The genetic architecture of human cortical folding', Science advances, vol. 7, no. 51, eabj9446, pp. 1-9. https://doi.org/10.1126/sciadv.abj9446

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T1 - The genetic architecture of human cortical folding

AU - Van Der Meer, Dennis

AU - Kaufmann, Tobias

AU - Shadrin, Alexey A.

AU - Makowski, Carolina

AU - Frei, Oleksandr

AU - Roelfs, Daniel

AU - Monereo-Sánchez, Jennifer

AU - Linden, David E.J.

AU - Rokicki, Jaroslav

AU - Alnæs, Dag

AU - De Leeuw, Christiaan

AU - Thompson, Wesley K.

AU - Loughnan, Robert

AU - Fan, Chun Chieh

AU - Westlye, Lars T.

AU - Andreassen, Ole A.

AU - Dale, Anders M.

N1 - Funding Information: The authors were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795, 298646, and 300767), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, 2017-004, and 2019-101), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC Starting Grant, grant agreement no. 802998), ERA-Net Cofund through the ERA PerMed project "Implement," and the National Institutes of Health (R01MH100351, R01GM104400, U24DA055330, R01MH111359, and U24DA041123; principal investigator: A.M.D.). Publisher Copyright: © 2021 American Association for the Advancement of Science. All rights reserved.

PY - 2021/12/17

Y1 - 2021/12/17

N2 - The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10-8). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.

AB - The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10-8). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.

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The genetic architecture of human cortical folding

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