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 - Quinlan, Erin Burke
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 - Martinot, Marie Laure Paillère
AU - Lemaitre, Hervé
AU - Nees, Frauke
AU - Orfanos, Dimitri Papadopoulos
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 - Funding Information:
We thank all investigators contributing to the Philadelphia Neurodevelopmental Cohort, especially Theodore D. Satterthwaite, for supporting this work. We thank Stephen M. Malone for supporting us in a multimodal investigation of CHRNA4. This work was supported by funding from The Feldman Family Foundation; the J.W. Bagley Foundation; the Medical Research Council (MRC grant MR/L016311/1). The IMAGEN consortium has received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviourinnormalbrainfunctionandpsychopathology;LSHM-CT-2007-037286),theHorizon2020fundedEuro-pean Research Council Advanced Grant STRATIFY (Brain network based stratification of reinforcement-related disorders; 695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways; PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics; MR/N027558/1), the FP7 projects IMAGEMEND(602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300-2), the Medical Research Council Grantc-VEDA(ConsortiumonVulnerabilitytoExternalizingDisordersandAddictions;MR/N000390/1),theSwedish ResearchCouncilFORMAS,theMedicalResearchCouncil,theNationalInstituteforHealthResearch(NIHR)Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministerium für Bildung und Forschung (BMBF Grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL), the Deutsche Forschungsgemeinschaft (DFG Grants SM 80/7-1, SM 80/7-2, SFB 940/1). Further support was provided by grants from: Agence Nationale de la Recherche (ANDR project AF12-NEUR0008-01-WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-ParisandInstitutNationaldelaSantéetdelaRechercheMédicale(INSERMinterfacegrant), Paris Sud University IDEX 2012; the National Institutes of Health (NIH), Science Foundation Ireland (16/ERCD/3797; Axon, Testosterone and Mental Health during Adolescence; Grant RO1 MH085772-01A1), and by NIH Consortium (Grant U54 EB020403), supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. A.A. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship.
Publisher Copyright:
© 2017 the authors.
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.
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.
KW - Alertness
KW - Cingulo-opercular network
KW - FMRI
KW - Genetics
KW - Nicotinic acetylcholine receptor
KW - Polymorphism
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U2 - 10.1523/JNEUROSCI.0991-17.2017
DO - 10.1523/JNEUROSCI.0991-17.2017
M3 - Article
C2 - 28877969
AN - SCOPUS:85030713429
SN - 0270-6474
VL - 37
SP - 9657
EP - 9666
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 40
ER -