Transcriptome-wide association study reveals two genes that influence mismatch negativity

Anjali Bhat; Haritz Irizar; Johan Hilge Thygesen; Karoline Kuchenbaecker; Oliver Pain; Rick A Adams; Eirini Zartaloudi; Jasmine Harju-Seppänen; Isabelle Austin-Zimmerman; Baihan Wang; Rebecca Muir; Ann Summerfelt; Xiaoming Michael Du; Heather Bruce; Patricio O'Donnell; Deepak P Srivastava; Karl Friston; L Elliot Hong; Mei-Hua Hall; Elvira Bramon

doi:10.1016/j.celrep.2021.108868

Transcriptome-wide association study reveals two genes that influence mismatch negativity

Cell Rep. 2021 Mar 16;34(11):108868. doi: 10.1016/j.celrep.2021.108868.

Authors

Anjali Bhat¹, Haritz Irizar², Johan Hilge Thygesen², Karoline Kuchenbaecker³, Oliver Pain⁴, Rick A Adams⁵, Eirini Zartaloudi², Jasmine Harju-Seppänen⁶, Isabelle Austin-Zimmerman², Baihan Wang², Rebecca Muir², Ann Summerfelt⁷, Xiaoming Michael Du⁷, Heather Bruce⁷, Patricio O'Donnell⁸, Deepak P Srivastava⁹, Karl Friston¹⁰, L Elliot Hong⁷, Mei-Hua Hall¹¹, Elvira Bramon¹²

Affiliations

¹ Division of Psychiatry, University College London, London, UK; Wellcome Centre for Human Neuroimaging, University College London, London, UK; Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK. Electronic address: anjali.bhat.14@ucl.ac.uk.
² Division of Psychiatry, University College London, London, UK.
³ Division of Psychiatry, University College London, London, UK; UCL Genetics Institute, University College London, London, UK.
⁴ Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
⁵ Division of Psychiatry, University College London, London, UK; Institute of Cognitive Neuroscience, University College London, London, UK.
⁶ Division of Psychiatry, University College London, London, UK; Department of Clinical, Educational and Health Psychology, University College London, London, UK.
⁷ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, MD, USA.
⁸ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, MD, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Takeda Pharmaceuticals, Cambridge, MA, USA.
⁹ Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
¹⁰ Wellcome Centre for Human Neuroimaging, University College London, London, UK.
¹¹ Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Psychosis Neurobiology Laboratory, McLean Hospital, Belmont, MA, USA.
¹² Division of Psychiatry, University College London, London, UK; Institute of Cognitive Neuroscience, University College London, London, UK; Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK; Camden and Islington NHS Foundation Trust, London, UK. Electronic address: e.bramon@ucl.ac.uk.

Abstract

Mismatch negativity (MMN) is a differential electrophysiological response measuring cortical adaptability to unpredictable stimuli. MMN is consistently attenuated in patients with psychosis. However, the genetics of MMN are uncharted, limiting the validation of MMN as a psychosis endophenotype. Here, we perform a transcriptome-wide association study of 728 individuals, which reveals 2 genes (FAM89A and ENGASE) whose expression in cortical tissues is associated with MMN. Enrichment analyses of neurodevelopmental expression signatures show that genes associated with MMN tend to be overexpressed in the frontal cortex during prenatal development but are significantly downregulated in adulthood. Endophenotype ranking value calculations comparing MMN and three other candidate psychosis endophenotypes (lateral ventricular volume and two auditory-verbal learning measures) find MMN to be considerably superior. These results yield promising insights into sensory processing in the cortex and endorse the notion of MMN as a psychosis endophenotype.

Keywords: Bayesian brain; MMN; endophenotype; gene expression; mismatch negativity; neurodevelopment; prediction error; psychosis; schizophrenia; transcriptome-wide association study.

Publication types

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

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Cerebral Ventricles / pathology
Child
Electrophysiological Phenomena / genetics
Female
Genome-Wide Association Study*
Humans
Intracellular Signaling Peptides and Proteins / genetics*
Intracellular Signaling Peptides and Proteins / metabolism
Intrinsically Disordered Proteins / genetics*
Intrinsically Disordered Proteins / metabolism
Male
Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / genetics*
Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / metabolism
Memory, Short-Term
Middle Aged
Neurotransmitter Agents / metabolism
Phenotype
Receptors, Virus / genetics*
Receptors, Virus / metabolism
Schizophrenia / physiopathology
Transcriptome / genetics*
Young Adult

Substances

FAM89A protein, human
Intracellular Signaling Peptides and Proteins
Intrinsically Disordered Proteins
Neurotransmitter Agents
Receptors, Virus
Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding