The molecular genetic landscape of human brain size variation

Jakob Seidlitz; Travis T. Mallard; Jacob W. Vogel; Younga H. Lee; Varun Warrier; Gareth Ball; Oskar Hansson; Leanna M. Hernandez; Ayan S. Mandal; Konrad Wagstyl; Michael V. Lombardo; Eric Courchesne; Joseph T. Glessner; Theodore D. Satterthwaite; Richard A.I. Bethlehem; Joshua D. Bernstock; Shinya Tasaki; Bernard Ng; Chris Gaiteri; Jordan W. Smoller; Tian Ge; Raquel E. Gur; Michael J. Gandal; A. F. Alexander-Bloch; Lifespan Brain Chart Consortium

doi:10.1016/j.celrep.2023.113439

The molecular genetic landscape of human brain size variation

Jakob Seidlitz, Travis T. Mallard, Jacob W. Vogel, Younga H. Lee, Varun Warrier, Gareth Ball, Oskar Hansson, Leanna M. Hernandez, Ayan S. Mandal, Konrad Wagstyl, Michael V. Lombardo, Eric Courchesne, Joseph T. Glessner, Theodore D. Satterthwaite, Richard A.I. Bethlehem, Joshua D. Bernstock, Shinya Tasaki, Bernard Ng, Chris Gaiteri, Jordan W. SmollerTian Ge, Raquel E. Gur, Michael J. Gandal, A. F. Alexander-Bloch, Lifespan Brain Chart Consortium

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

Abstract

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.

Original language	English
Article number	113439
Journal	Cell Reports
Volume	42
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2023.113439
Publication status	Published - 2023 Nov 28

Bibliographical note

Funding Information:
The authors would like to acknowledge the various open science initiatives, and their associated funding, that provided the necessary datasets used in this manuscript. J.S. and J.W.V. were supported by NIMH T32MH019112. A.F.A.-B. and J.S. were supported by NIMH K08MH120564. T.T.M. was supported by NHGRI T32HG010464. V.W. was supported by St. Catharine's College Cambridge. R.A.I.B. was supported by the Autism Research Trust. K.W. was supported by the Wellcome Trust (215901/Z/19/Z). T.D.S. was supported by NIH R01MH113550, R01MH120482, R01MH112847, R01EB022573, RF1MH121867, and R37MH125829. G.B. was supported by the Australian National Health and Medical Research Council (NHMRC; Investigator Grant 1194497). We thank Mass General Brigham Biobank for providing genomic and health information data. Conceptualization, J.S. and A.F.A.-B.; methodology, J.S. T.T.M. M.J.G. and A.F.A.-B.; formal analysis, J.S. T.T.M. Y.H.L. L.M.H. S.T. B.N. C.G. T.G. and M.J.G.; resources, J.S. T.T.M. V.W. R.A.I.B. J.W.S. T.G. M.J.G. and A.F.A.-B.; data curation, J.S. T.T.M. J.W.V. Y.H.L. V.W. R.A.I.B. S.T. B.N. C.G. T.G. and M.J.G.; writing – original draft, J.S. T.T.M. M.J.G. and A.F.A.-B.; writing – review & editing, all authors; visualization, J.S. and T.T.M.; supervision, M.J.G. and A.F.A.-B.; project administration, J.S. and A.F.A.-B.; funding acquisition, J.S. and A.F.A.-B. J.S. R.A.I.B. J.D.B. and A.F.A.-B. are directors and hold equity in Centile Bioscience. J.D.B. holds positions/equity in UpFront Diagnostics, Treovir, and NeuroX1. A.F.A.-B. receives consulting income from Octave Bioscience. We support inclusive, diverse, and equitable conduct of research.

Funding Information:
The authors would like to acknowledge the various open science initiatives, and their associated funding, that provided the necessary datasets used in this manuscript. J.S. and J.W.V. were supported by NIMH T32MH019112 . A.F.A.-B. and J.S. were supported by NIMH K08MH120564 . T.T.M. was supported by NHGRI T32HG010464 . V.W. was supported by St. Catharine’s College Cambridge . R.A.I.B. was supported by the Autism Research Trust . K.W. was supported by the Wellcome Trust ( 215901/Z/19/Z ). T.D.S. was supported by NIH R01MH113550 , R01MH120482 , R01MH112847 , R01EB022573 , RF1MH121867 , and R37MH125829 . G.B. was supported by the Australian National Health and Medical Research Council (NHMRC; Investigator Grant 1194497 ). We thank Mass General Brigham Biobank for providing genomic and health information data.

Publisher Copyright:
© 2023 The Authors

Subject classification (UKÄ)

Medical Genetics

Free keywords

brain development
CP: Neuroscience
imaging genetics
psychiatric disorders
transcriptomics
TWAS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2023.113439

Cite this

Seidlitz, J., Mallard, T. T., Vogel, J. W., Lee, Y. H., Warrier, V., Ball, G., Hansson, O., Hernandez, L. M., Mandal, A. S., Wagstyl, K., Lombardo, M. V., Courchesne, E., Glessner, J. T., Satterthwaite, T. D., Bethlehem, R. A. I., Bernstock, J. D., Tasaki, S., Ng, B., Gaiteri, C., ... Lifespan Brain Chart Consortium (2023). The molecular genetic landscape of human brain size variation. Cell Reports, 42(11), Article 113439. https://doi.org/10.1016/j.celrep.2023.113439

@article{fd63c7ba822e4722a349d065e7f7097c,

title = "The molecular genetic landscape of human brain size variation",

abstract = "Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.",

keywords = "brain development, CP: Neuroscience, imaging genetics, psychiatric disorders, transcriptomics, TWAS",

author = "Jakob Seidlitz and Mallard, {Travis T.} and Vogel, {Jacob W.} and Lee, {Younga H.} and Varun Warrier and Gareth Ball and Oskar Hansson and Hernandez, {Leanna M.} and Mandal, {Ayan S.} and Konrad Wagstyl and Lombardo, {Michael V.} and Eric Courchesne and Glessner, {Joseph T.} and Satterthwaite, {Theodore D.} and Bethlehem, {Richard A.I.} and Bernstock, {Joshua D.} and Shinya Tasaki and Bernard Ng and Chris Gaiteri and Smoller, {Jordan W.} and Tian Ge and Gur, {Raquel E.} and Gandal, {Michael J.} and Alexander-Bloch, {A. F.} and {Lifespan Brain Chart Consortium}",

note = "Funding Information: The authors would like to acknowledge the various open science initiatives, and their associated funding, that provided the necessary datasets used in this manuscript. J.S. and J.W.V. were supported by NIMH T32MH019112. A.F.A.-B. and J.S. were supported by NIMH K08MH120564. T.T.M. was supported by NHGRI T32HG010464. V.W. was supported by St. Catharine's College Cambridge. R.A.I.B. was supported by the Autism Research Trust. K.W. was supported by the Wellcome Trust (215901/Z/19/Z). T.D.S. was supported by NIH R01MH113550, R01MH120482, R01MH112847, R01EB022573, RF1MH121867, and R37MH125829. G.B. was supported by the Australian National Health and Medical Research Council (NHMRC; Investigator Grant 1194497). We thank Mass General Brigham Biobank for providing genomic and health information data. Conceptualization, J.S. and A.F.A.-B.; methodology, J.S. T.T.M. M.J.G. and A.F.A.-B.; formal analysis, J.S. T.T.M. Y.H.L. L.M.H. S.T. B.N. C.G. T.G. and M.J.G.; resources, J.S. T.T.M. V.W. R.A.I.B. J.W.S. T.G. M.J.G. and A.F.A.-B.; data curation, J.S. T.T.M. J.W.V. Y.H.L. V.W. R.A.I.B. S.T. B.N. C.G. T.G. and M.J.G.; writing – original draft, J.S. T.T.M. M.J.G. and A.F.A.-B.; writing – review & editing, all authors; visualization, J.S. and T.T.M.; supervision, M.J.G. and A.F.A.-B.; project administration, J.S. and A.F.A.-B.; funding acquisition, J.S. and A.F.A.-B. J.S. R.A.I.B. J.D.B. and A.F.A.-B. are directors and hold equity in Centile Bioscience. J.D.B. holds positions/equity in UpFront Diagnostics, Treovir, and NeuroX1. A.F.A.-B. receives consulting income from Octave Bioscience. We support inclusive, diverse, and equitable conduct of research. Funding Information: The authors would like to acknowledge the various open science initiatives, and their associated funding, that provided the necessary datasets used in this manuscript. J.S. and J.W.V. were supported by NIMH T32MH019112 . A.F.A.-B. and J.S. were supported by NIMH K08MH120564 . T.T.M. was supported by NHGRI T32HG010464 . V.W. was supported by St. Catharine{\textquoteright}s College Cambridge . R.A.I.B. was supported by the Autism Research Trust . K.W. was supported by the Wellcome Trust ( 215901/Z/19/Z ). T.D.S. was supported by NIH R01MH113550 , R01MH120482 , R01MH112847 , R01EB022573 , RF1MH121867 , and R37MH125829 . G.B. was supported by the Australian National Health and Medical Research Council (NHMRC; Investigator Grant 1194497 ). We thank Mass General Brigham Biobank for providing genomic and health information data. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2023.113439",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

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Seidlitz, J, Mallard, TT, Vogel, JW, Lee, YH, Warrier, V, Ball, G, Hansson, O, Hernandez, LM, Mandal, AS, Wagstyl, K, Lombardo, MV, Courchesne, E, Glessner, JT, Satterthwaite, TD, Bethlehem, RAI, Bernstock, JD, Tasaki, S, Ng, B, Gaiteri, C, Smoller, JW, Ge, T, Gur, RE, Gandal, MJ, Alexander-Bloch, AF & Lifespan Brain Chart Consortium 2023, 'The molecular genetic landscape of human brain size variation', Cell Reports, vol. 42, no. 11, 113439. https://doi.org/10.1016/j.celrep.2023.113439

TY - JOUR

T1 - The molecular genetic landscape of human brain size variation

AU - Seidlitz, Jakob

AU - Mallard, Travis T.

AU - Vogel, Jacob W.

AU - Lee, Younga H.

AU - Warrier, Varun

AU - Ball, Gareth

AU - Hansson, Oskar

AU - Hernandez, Leanna M.

AU - Mandal, Ayan S.

AU - Wagstyl, Konrad

AU - Lombardo, Michael V.

AU - Courchesne, Eric

AU - Glessner, Joseph T.

AU - Satterthwaite, Theodore D.

AU - Bethlehem, Richard A.I.

AU - Bernstock, Joshua D.

AU - Tasaki, Shinya

AU - Ng, Bernard

AU - Gaiteri, Chris

AU - Smoller, Jordan W.

AU - Ge, Tian

AU - Gur, Raquel E.

AU - Gandal, Michael J.

AU - Alexander-Bloch, A. F.

AU - Lifespan Brain Chart Consortium

N1 - Funding Information: The authors would like to acknowledge the various open science initiatives, and their associated funding, that provided the necessary datasets used in this manuscript. J.S. and J.W.V. were supported by NIMH T32MH019112. A.F.A.-B. and J.S. were supported by NIMH K08MH120564. T.T.M. was supported by NHGRI T32HG010464. V.W. was supported by St. Catharine's College Cambridge. R.A.I.B. was supported by the Autism Research Trust. K.W. was supported by the Wellcome Trust (215901/Z/19/Z). T.D.S. was supported by NIH R01MH113550, R01MH120482, R01MH112847, R01EB022573, RF1MH121867, and R37MH125829. G.B. was supported by the Australian National Health and Medical Research Council (NHMRC; Investigator Grant 1194497). We thank Mass General Brigham Biobank for providing genomic and health information data. Conceptualization, J.S. and A.F.A.-B.; methodology, J.S. T.T.M. M.J.G. and A.F.A.-B.; formal analysis, J.S. T.T.M. Y.H.L. L.M.H. S.T. B.N. C.G. T.G. and M.J.G.; resources, J.S. T.T.M. V.W. R.A.I.B. J.W.S. T.G. M.J.G. and A.F.A.-B.; data curation, J.S. T.T.M. J.W.V. Y.H.L. V.W. R.A.I.B. S.T. B.N. C.G. T.G. and M.J.G.; writing – original draft, J.S. T.T.M. M.J.G. and A.F.A.-B.; writing – review & editing, all authors; visualization, J.S. and T.T.M.; supervision, M.J.G. and A.F.A.-B.; project administration, J.S. and A.F.A.-B.; funding acquisition, J.S. and A.F.A.-B. J.S. R.A.I.B. J.D.B. and A.F.A.-B. are directors and hold equity in Centile Bioscience. J.D.B. holds positions/equity in UpFront Diagnostics, Treovir, and NeuroX1. A.F.A.-B. receives consulting income from Octave Bioscience. We support inclusive, diverse, and equitable conduct of research. Funding Information: The authors would like to acknowledge the various open science initiatives, and their associated funding, that provided the necessary datasets used in this manuscript. J.S. and J.W.V. were supported by NIMH T32MH019112 . A.F.A.-B. and J.S. were supported by NIMH K08MH120564 . T.T.M. was supported by NHGRI T32HG010464 . V.W. was supported by St. Catharine’s College Cambridge . R.A.I.B. was supported by the Autism Research Trust . K.W. was supported by the Wellcome Trust ( 215901/Z/19/Z ). T.D.S. was supported by NIH R01MH113550 , R01MH120482 , R01MH112847 , R01EB022573 , RF1MH121867 , and R37MH125829 . G.B. was supported by the Australian National Health and Medical Research Council (NHMRC; Investigator Grant 1194497 ). We thank Mass General Brigham Biobank for providing genomic and health information data. Publisher Copyright: © 2023 The Authors

PY - 2023/11/28

Y1 - 2023/11/28

N2 - Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.

AB - Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.

KW - brain development

KW - CP: Neuroscience

KW - imaging genetics

KW - psychiatric disorders

KW - transcriptomics

KW - TWAS

U2 - 10.1016/j.celrep.2023.113439

DO - 10.1016/j.celrep.2023.113439

M3 - Article

C2 - 37963017

AN - SCOPUS:85176956103

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113439

ER -

The molecular genetic landscape of human brain size variation

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

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