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; Lifespan Brain Chart Consortium; Shinya Tasaki; Bernard Ng; Chris Gaiteri; Jordan W Smoller; Tian Ge; Raquel E Gur; Michael J Gandal; Aaron F Alexander-Bloch

doi:10.1016/j.celrep.2023.113439

The molecular genetic landscape of human brain size variation

Cell Rep. 2023 Nov 28;42(11):113439. doi: 10.1016/j.celrep.2023.113439. Epub 2023 Nov 14.

Authors

Jakob Seidlitz¹, Travis T Mallard², Jacob W Vogel³, Younga H Lee², Varun Warrier⁴, Gareth Ball⁵, Oskar Hansson⁶, Leanna M Hernandez⁷, Ayan S Mandal⁸, Konrad Wagstyl⁹, Michael V Lombardo¹⁰, Eric Courchesne¹¹, Joseph T Glessner¹², Theodore D Satterthwaite¹³, Richard A I Bethlehem¹⁴, Joshua D Bernstock¹⁵; Lifespan Brain Chart Consortium; Shinya Tasaki¹⁶, Bernard Ng¹⁶, Chris Gaiteri¹⁶, Jordan W Smoller¹⁷, Tian Ge¹⁷, Raquel E Gur⁸, Michael J Gandal¹⁸, Aaron F Alexander-Bloch⁸

Affiliations

¹ Lifespan Brain Institute, The Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Child and Adolescent Psychiatry and Behavioral Science, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jakob.seidlitz@pennmedicine.upenn.edu.
² Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA 02142, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02142, USA.
³ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA; Lifespan Informatics and Neuroimaging Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
⁴ Department of Psychiatry, University of Cambridge, Cambridge CB2 1TN, UK; Department of Psychology, University of Cambridge, Cambridge CB2 1TN, UK.
⁵ Developmental Imaging, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Melbourne, VIC 3052, Australia.
⁶ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö P663+Q9, Sweden; Memory Clinic, Skåne University Hospital, Malmö P663+Q9, Sweden.
⁷ Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90024, USA.
⁸ Lifespan Brain Institute, The Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Child and Adolescent Psychiatry and Behavioral Science, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Wellcome Centre for Human Neuroimaging, University College London, London WC1N 3AR, UK.
¹⁰ Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy.
¹¹ Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Autism Center of Excellence, University of California, San Diego, San Diego, CA 92093, USA.
¹² The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹³ Lifespan Brain Institute, The Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA; Lifespan Informatics and Neuroimaging Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
¹⁴ Department of Psychiatry, University of Cambridge, Cambridge CB2 1TN, UK.
¹⁵ Department of Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital, Harvard University, Boston, MA 02115, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
¹⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA 02142, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02142, USA; Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁸ Lifespan Brain Institute, The Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.

PMID: 37963017
DOI: 10.1016/j.celrep.2023.113439

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: CP: Neuroscience; TWAS; brain development; imaging genetics; psychiatric disorders; transcriptomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Brain* / metabolism
Genetic Predisposition to Disease
Genome-Wide Association Study / methods
Humans
Molecular Biology
Organ Size
Phenotype
Transcriptome*

Abstract

Publication types

MeSH terms

Grants and funding