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, Jahrgang 37, Nr. 40, 04.10.2017, S. 9657-9666.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -