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

Sepideh Sadaghiani, Bernard Ng, Andre Altmann, Jean-Baptiste Poline, Tobias Banaschewski, Arun L.W. Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Patricia Conrod, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Jürgen Gallinat, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Hervé Lemaitre, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Sabina Millenet, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Valerio Napolioni, Michael Greicius
J. Neurosci.. 2017-09-06; 37(40): 9657-9666
DOI: 10.1523/JNEUROSCI.0991-17.2017

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Comment in
J Neurosci. 2018 Jan 10;38(2):257-259.

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.

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Auteurs Bordeaux Neurocampus