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. 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

Sepideh Sadaghiani  1   2   3 , Bernard Ng  4   5 , Andre Altmann  4   6 , Jean-Baptiste Poline  7 , Tobias Banaschewski  8 , Arun L W Bokde  9 , Uli Bromberg  10 , Christian Büchel  10 , Erin Burke Quinlan  11 , Patricia Conrod  11 , Sylvane Desrivières  11 , Herta Flor  12   13 , Vincent Frouin  14 , Hugh Garavan  15 , Penny Gowland  16 , Jürgen Gallinat  17 , Andreas Heinz  17 , Bernd Ittermann  18 , Jean-Luc Martinot  19   20   21   22 , Marie-Laure Paillère Martinot  20   23 , Hervé Lemaitre  19 , Frauke Nees  8   12 , Dimitri Papadopoulos Orfanos  14 , Tomáš Paus  24 , Luise Poustka  25   26 , Sabina Millenet  8 , Juliane H Fröhner  27 , Michael N Smolka  27 , Henrik Walter  17 , Robert Whelan  28 , Gunter Schumann  11 , Valerio Napolioni  4 , Michael Greicius  4
Affiliations

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

Sepideh Sadaghiani et al. J Neurosci. .

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.

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Figures

Figure 1.
Figure 1.
Heterozygotes at the CHRNA4 SNP have increased CO network activation. A, CO network volume of interest in the FINDlab atlas based on intrinsic functional connectivity (Shirer et al., 2012). B, Estimated brain activation averaged across the CO network volume of interest in the IMAGEN cohort during the stop signal task. Higher CO network activation is observed in heterozygotes compared with homozygous T/T and C/C carriers. In boxes, the central mark indicates the median and the bottom and top edges indicate 25th and 75th percentiles, respectively. The whiskers extend to the most extreme data points not considered outliers (within 1.5 interquartile range of the bottom and top of box),and the outliers are marked by “+”. C, Genotype contrast T/C > homozygotes for activation in the CO network and three other networks for comparison: FP, Frontoparietal; DAT, dorsal attention; DM, default mode. A significant overdominant effect was observed for the CO network only. Error bars indicate SE.
Figure 2.
Figure 2.
Whole-brain map showing that activation differences across genotypes overlap with the CO network. Shown is the contrast T/C larger than homozygous T/T and C/C carriers in the IMAGEN cohort during the stop signal task (p < 0.005 auxiliary uncorrected threshold, corrected at cluster level). Blue shows the CO volume of interest as in Figure 1; red shows areas of higher activation in heterozygotes displayed on a canonical single subject structural image demonstrating the overlap in dorsal anterior cingulate, anterior prefrontal, and anterior insula loci.
Figure 3.
Figure 3.
Increased CO network activation in heterozygotes is replicated in the PNC cohort. A, Estimated brain activation averaged across the CO network volume of interest in the PNC cohort during the fractal n-back task is shown separately for each genotype. Higher CO network activation is observed in heterozygotes compared with homozygous T/T and C/C carriers. Box plots are arranged as explained in Figure 1. B, Genotype contrast T/C > homozygotes is shown for activation in the CO network and three other networks for comparison (abbreviations as in Fig. 1). A significant overdominant effect was observed for the CO network only. Error bars indicate SE.
Figure 4.
Figure 4.
Impact of genotype on tonic alertness capacity shows an overdominant effect. Performance accuracy in CPTs as measured by perceptual sensitivity is shown for the IMAGEN (A) and PNC (B) cohorts for the three rs1044396 genotypes. In both datasets, heterozygotes performed better than homozygote carriers of the major (“T”) or minor (“C”) allele. Box plots are arranged as explained in Figure 1.
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