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J Neurosci. 2017 Oct 4;37(40):9657-9666. doi: 10.1523/JNEUROSCI.0991-17.2017. Epub 2017 Sep 6.

Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control.

Author information

1
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, Sepideh@illinois.edu.
2
Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
3
Beckman Institute for Advanced Science and Technology, Urbana, Illinois 61801.
4
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305.
5
Department of Statistics, University of British Columbia, Vancouver BC V6T 1Z4, Canada.
6
Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Bioengineering, University College London, London WC1E 6BT, United Kingdom.
7
Department of Psychology, University of California, Berkeley, California 94720.
8
Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
9
Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
10
University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
11
Medical Research Council, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London WC2R 2LS, United Kingdom.
12
Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
13
Department of Psychology, School of Social Sciences, University of Mannheim, 68131 Mannheim, Germany.
14
NeuroSpin, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France.
15
Departments of Psychiatry and Psychology, University of Vermont, Burlington, Vermont 05405.
16
Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
17
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany.
18
Physikalisch-Technische Bundesanstalt, 10587 Berlin, Germany.
19
Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 "Neuroimaging & Psychiatry", University Paris Sud - Paris Saclay, 91400 Orsay, France.
20
University Paris Descartes, 75006 Paris, France.
21
Service Hospitalier Frédéric Joliot, 91400 Orsay, France.
22
Maison de Solenn, Cochin Hospital, 75014 Paris, France.
23
AP-HP, Department of Adolescent Psychopathology and Medicine, Maison de Solenn, Cochin Hospital, 75014 Paris, France.
24
Rotman Research Institute, Baycrest and Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario M6A 2E1, Canada.
25
Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, 37075 Göttingen, Germany.
26
Clinic for Child and Adolescent Psychiatry, Medical University of Vienna, 1090 Vienna, Austria.
27
Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, 01069 Dresden, Germany, and.
28
School of Psychology and Global Brain Health Institute, Trinity College Dublin 2, Ireland.

Abstract

The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N = 1586, behavioral total N = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence p = 1.33 * 10-5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities.SIGNIFICANCE STATEMENT The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes and is dysregulated in several neuropsychiatric disorders. Despite this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show the impact of a common polymorphism of the high-affinity nicotinic receptor α4β2 that is consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance and higher behavioral alertness performance than both homozygous groups. This gene-brain-behavior relationship informs about the biological basis of interindividual differences in cognitive control.

KEYWORDS:

alertness; cingulo-opercular network; fMRI; genetics; nicotinic acetylcholine receptor; polymorphism

PMID:
28877969
PMCID:
PMC6596609
DOI:
10.1523/JNEUROSCI.0991-17.2017
[Indexed for MEDLINE]
Free PMC Article

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