Cell Reports (Nov 2023)
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,
- Aaron F. Alexander-Bloch
Affiliations
- Jakob Seidlitz
- 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; Corresponding author
- Travis T. Mallard
- 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
- Jacob W. Vogel
- 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
- Younga H. Lee
- 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
- Varun Warrier
- Department of Psychiatry, University of Cambridge, Cambridge CB2 1TN, UK; Department of Psychology, University of Cambridge, Cambridge CB2 1TN, UK
- Gareth Ball
- Developmental Imaging, Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Melbourne, VIC 3052, Australia
- Oskar Hansson
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö P663+Q9, Sweden; Memory Clinic, Skåne University Hospital, Malmö P663+Q9, Sweden
- Leanna M. Hernandez
- Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90024, USA
- Ayan S. Mandal
- 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
- Konrad Wagstyl
- Wellcome Centre for Human Neuroimaging, University College London, London WC1N 3AR, UK
- Michael V. Lombardo
- Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy
- Eric Courchesne
- 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
- Joseph T. Glessner
- 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
- Theodore D. Satterthwaite
- 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
- Richard A.I. Bethlehem
- Department of Psychiatry, University of Cambridge, Cambridge CB2 1TN, UK
- Joshua D. Bernstock
- 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
- Shinya Tasaki
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
- Bernard Ng
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
- Chris Gaiteri
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
- Jordan W. Smoller
- 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
- Tian Ge
- 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
- Raquel E. Gur
- 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
- Michael J. Gandal
- 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
- Aaron F. Alexander-Bloch
- 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
- Journal volume & issue
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Vol. 42,
no. 11
p. 113439
Abstract
Summary: 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.
