Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

Rebecca L Walker; Gokul Ramaswami; Christopher Hartl; Nicholas Mancuso; Michael J Gandal; Luis de la Torre-Ubieta; Bogdan Pasaniuc; Jason L Stein; Daniel H Geschwind

doi:10.1016/j.cell.2019.09.021

Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

Cell. 2019 Oct 17;179(3):750-771.e22. doi: 10.1016/j.cell.2019.09.021.

Authors

Rebecca L Walker¹, Gokul Ramaswami², Christopher Hartl³, Nicholas Mancuso⁴, Michael J Gandal⁵, Luis de la Torre-Ubieta⁶, Bogdan Pasaniuc⁷, Jason L Stein⁸, Daniel H Geschwind⁹

Affiliations

¹ Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
³ Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024, USA.
⁵ Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
⁶ Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
⁷ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Genetics and UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.

Abstract

Tissue-specific regulatory regions harbor substantial genetic risk for disease. Because brain development is a critical epoch for neuropsychiatric disease susceptibility, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7,962 expression quantitative trait loci (eQTL) and 4,635 spliceQTL (sQTL), including several thousand prenatal-specific regulatory regions. We show that significant genetic liability for neuropsychiatric disease lies within prenatal eQTL and sQTL. Integration of eQTL and sQTL with genome-wide association studies (GWAS) via transcriptome-wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in schizophrenia (SCZ). Gene network analysis revealed that SCZ and autism spectrum disorder (ASD) affect distinct developmental gene co-expression modules. Yet, in each disorder, common and rare genetic variation converges within modules, which in ASD implicates superficial cortical neurons. More broadly, these data, available as a web browser and our analyses, demonstrate the genetic mechanisms by which developmental events have a widespread influence on adult anatomical and behavioral phenotypes.

Keywords: TWAS; autism; eQTL; gene networks; gene regulation; human cortical development; sQTL; schizophrenia; splicing regulation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Autism Spectrum Disorder / genetics*
Autism Spectrum Disorder / metabolism
Autism Spectrum Disorder / pathology
Brain / growth & development
Brain / metabolism
Female
Fetus / metabolism
Gene Expression Regulation, Developmental
Genetic Predisposition to Disease
Genome-Wide Association Study
Gestational Age
Humans
Male
Neurons / metabolism
Polymorphism, Single Nucleotide / genetics
Quantitative Trait Loci / genetics*
RNA Splicing / genetics
Schizophrenia / genetics*
Schizophrenia / metabolism
Schizophrenia / pathology
Transcriptome / genetics*

Abstract

Publication types

MeSH terms

Grants and funding