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
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305,
Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
J Neurosci. 2017 Oct 4;37(40):9657-9666. doi: 10.1523/JNEUROSCI.0991-17.2017. Epub 2017 Sep 6.
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 = 1586, behavioral total = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the 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 = 1.33 * 10). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating expression levels. This is the first report of overdominance in the nicotinic system. These findings connect genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities. 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.
烟碱系统在认知控制中发挥着重要作用，并与多种神经精神疾病有关。然而，该系统中的基因变异对个体认知控制能力的贡献却知之甚少，介导这种基因贡献的大脑过程在很大程度上仍未明确。在这项关于人类烟碱受体系统的首次大规模神经影像遗传学研究中（两个队列，包括男性和女性，功能磁共振成像研究对象共1586人，行为学研究对象共3650人），我们研究了高亲和力烟碱受体α4β2的一种常见多态性（基因上的rs1044396），该多态性先前在行为学和尼古丁相关研究中有所涉及（尽管主要/次要等位基因的影响并不一致）。基于我们之前的神经影像研究结果，我们预期这种多态性会影响扣带 - 脑岛网络（CO）中的神经活动，该网络参与包括维持警觉在内的核心认知控制过程。在两个队列中均发现，在认知活动期间，与两种纯合子相比，CO网络的所有皮质区域在杂合子中表现出更高的活性。这种倒U形关系反映了超显性效应；也就是说，等位基因相互作用（累积证据 = 1.33 * 10）。此外，杂合子在主要依赖持续警觉的行为任务中表现得更准确。在周围区域的单倍型上未观察到影响，这支持了rs1044396处真正的超显性效应。作为一种可能的机制，我们观察到这种多态性是一个调节表达水平的表达数量性状位点。这是烟碱系统中超显性的首次报道。这些发现将基因型、CO网络激活和持续警觉联系起来，为基因如何塑造个体的认知控制能力提供了见解。烟碱乙酰胆碱系统在认知控制过程的神经调节中起着核心作用，并且在几种神经精神疾病中失调。尽管具有这种功能重要性，但尚无大规模神经影像遗传学研究针对该系统中的基因变异对人类大脑活动的贡献。在此，我们展示了高亲和力烟碱受体α4β2的一种常见多态性在两个大型人类队列中的大脑活动和行为上的一致影响。我们报道了该位点迄今未知的超显性效应（等位基因相互作用），其中杂合子在维持警觉的扣带 - 脑岛网络中表现出更高的活性，并且在行为警觉表现上高于两个纯合组。这种基因 - 大脑 - 行为关系揭示了认知控制中个体差异的生物学基础。
