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

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Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control. / Sadaghiani, Sepideh; Ng, Bernard; Altmann, Andre; Poline, Jean-Baptiste; Banaschewski, Tobias; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Burke Quinlan, Erin; Conrod, Patricia; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Gallinat, Jürgen; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Lemaitre, Hervé; Nees, Frauke; Papadopoulos Orfanos, Dimitri; Paus, Tomáš; Poustka, Luise; Millenet, Sabina; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Napolioni, Valerio; Greicius, Michael.

In: J NEUROSCI, Vol. 37, No. 40, 04.10.2017, p. 9657-9666.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sadaghiani, S, Ng, B, Altmann, A, Poline, J-B, Banaschewski, T, Bokde, ALW, Bromberg, U, Büchel, C, Burke Quinlan, E, Conrod, P, Desrivières, S, Flor, H, Frouin, V, Garavan, H, Gowland, P, Gallinat, J, Heinz, A, Ittermann, B, Martinot, J-L, Paillère Martinot, M-L, Lemaitre, H, Nees, F, Papadopoulos Orfanos, D, Paus, T, Poustka, L, Millenet, S, Fröhner, JH, Smolka, MN, Walter, H, Whelan, R, Schumann, G, Napolioni, V & Greicius, M 2017, 'Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control', J NEUROSCI, vol. 37, no. 40, pp. 9657-9666. https://doi.org/10.1523/JNEUROSCI.0991-17.2017

APA

Sadaghiani, S., Ng, B., Altmann, A., Poline, J-B., Banaschewski, T., Bokde, A. L. W., Bromberg, U., Büchel, C., Burke Quinlan, E., Conrod, P., Desrivières, S., Flor, H., Frouin, V., Garavan, H., Gowland, P., Gallinat, J., Heinz, A., Ittermann, B., Martinot, J-L., ... Greicius, M. (2017). Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control. J NEUROSCI, 37(40), 9657-9666. https://doi.org/10.1523/JNEUROSCI.0991-17.2017

Vancouver

Sadaghiani S, Ng B, Altmann A, Poline J-B, Banaschewski T, Bokde ALW et al. Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control. J NEUROSCI. 2017 Oct 4;37(40):9657-9666. https://doi.org/10.1523/JNEUROSCI.0991-17.2017

Bibtex

@article{acbc8167f508438d935893bb6c28f59a,
title = "Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control",
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 = "Adolescent, Cerebral Cortex, Cognition, Cohort Studies, Female, Frontal Lobe, Genetic Association Studies, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Nerve Net, Photic Stimulation, Polymorphism, Single Nucleotide, Psychomotor Performance, Receptors, Nicotinic, Journal Article",
author = "Sepideh Sadaghiani and Bernard Ng and Andre Altmann and Jean-Baptiste Poline and Tobias Banaschewski and Bokde, {Arun L W} and Uli Bromberg and Christian B{\"u}chel and {Burke Quinlan}, Erin and Patricia Conrod and Sylvane Desrivi{\`e}res and Herta Flor and Vincent Frouin and Hugh Garavan and Penny Gowland and J{\"u}rgen Gallinat and Andreas Heinz and Bernd Ittermann and Jean-Luc Martinot and {Paill{\`e}re Martinot}, Marie-Laure and Herv{\'e} Lemaitre and Frauke Nees and {Papadopoulos Orfanos}, Dimitri and Tom{\'a}{\v s} Paus and Luise Poustka and Sabina Millenet and Fr{\"o}hner, {Juliane H} and Smolka, {Michael N} and Henrik Walter and Robert Whelan and Gunter Schumann and Valerio Napolioni and Michael Greicius",
note = "Copyright {\textcopyright} 2017 the authors 0270-6474/17/379658-10$15.00/0.",
year = "2017",
month = oct,
day = "4",
doi = "10.1523/JNEUROSCI.0991-17.2017",
language = "English",
volume = "37",
pages = "9657--9666",
journal = "J NEUROSCI",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "40",

}

RIS

TY - JOUR

T1 - Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control

AU - Sadaghiani, Sepideh

AU - Ng, Bernard

AU - Altmann, Andre

AU - Poline, Jean-Baptiste

AU - Banaschewski, Tobias

AU - Bokde, Arun L W

AU - Bromberg, Uli

AU - Büchel, Christian

AU - Burke Quinlan, Erin

AU - Conrod, Patricia

AU - Desrivières, Sylvane

AU - Flor, Herta

AU - Frouin, Vincent

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Gallinat, Jürgen

AU - Heinz, Andreas

AU - Ittermann, Bernd

AU - Martinot, Jean-Luc

AU - Paillère Martinot, Marie-Laure

AU - Lemaitre, Hervé

AU - Nees, Frauke

AU - Papadopoulos Orfanos, Dimitri

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Millenet, Sabina

AU - Fröhner, Juliane H

AU - Smolka, Michael N

AU - Walter, Henrik

AU - Whelan, Robert

AU - Schumann, Gunter

AU - Napolioni, Valerio

AU - Greicius, Michael

N1 - Copyright © 2017 the authors 0270-6474/17/379658-10$15.00/0.

PY - 2017/10/4

Y1 - 2017/10/4

N2 - 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.

AB - 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.

KW - Adolescent

KW - Cerebral Cortex

KW - Cognition

KW - Cohort Studies

KW - Female

KW - Frontal Lobe

KW - Genetic Association Studies

KW - Gyrus Cinguli

KW - Humans

KW - Magnetic Resonance Imaging

KW - Male

KW - Nerve Net

KW - Photic Stimulation

KW - Polymorphism, Single Nucleotide

KW - Psychomotor Performance

KW - Receptors, Nicotinic

KW - Journal Article

U2 - 10.1523/JNEUROSCI.0991-17.2017

DO - 10.1523/JNEUROSCI.0991-17.2017

M3 - SCORING: Journal article

C2 - 28877969

VL - 37

SP - 9657

EP - 9666

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 40

ER -