Abstract
The serotonin transporter-linked polymorphic region 5-HTTLPR is a key genetic regulator of 5-HTT expression in the human brain where the short allele S has been implicated in emotion dysregulation. However, the neural mechanism underlying the association between this variant and emotion processing is still unclear. Earlier studies suggested an effect of 5-HTTLPR on amygdala activation during emotional face processing. However, this association has been questioned in recent studies employing larger sample sizes and meta-analyses. Here, we examined a sample of 223 healthy subjects with a well-established fMRI emotional face processing task to (1) re-evaluate the association between 5-HTTLPR and amygdala activation, (2) explore potential network-based functional connectivity phenotypes for associations with 5-HTTLPR, and (3) probe the reliability, behavioral significance and potential structural confounds of the identified network phenotype. Our results revealed no significant effect of 5-HTTLPR on amygdala activation (P>0.79). However, the number of S alleles was significantly correlated with functional connectivity of a visual-limbic subnetwork (PFWE=0.03). The subnetwork cluster included brain regions that are pivotal to emotion regulation such as the hippocampus, orbitofrontal cortex, anterior cingulate gyrus, fusiform gyrus, and subcortex. Notably, individuals with lower subnetwork connectivity had significantly higher emotion suppression scores (P=0.01). Further, the connectivity metrics were test–retest reliable and independent from subnetwork gray matter volume and white matter anisotropy. Our data provide evidence for a functional network-based phenotype linking genetic variation in 5-HTTLPR to emotion regulation, and suggest that further critical evaluations of the association between 5-HTTLPR and amygdala activation are warranted.
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Acknowledgements
This study is supported by the German Federal Ministry of Education and Research (IntegraMent: grants 01ZX1314A, 01ZX1314B and 01ZX1314G to MMN, SC, MR, AM-L, HW, and AH; NGFNplus MooDS: grants 01GS08144, 01GS08147, 01GS08148 to MMN, SC, HW, MR, AM-L and AH), the European Community’s Seventh Framework Programme under the grant agreements No. 115300 (Project EU-AIMS to AM-L), No 115008 (Project EU-NEWMEDS to AM-L), No. 602805 (Project EU-AGGRESSOTYPE to AM-L) and No. 602450 (Project EU-IMAGEMEND to AM-L), and the German Research Foundation (DFG; grant FOR2107; RI908/11-1 to MR; WI3429/3-1 to SHW). HT acknowledges grant support by the German Federal Ministry of Education and Research (grant 01GQ1102). We thank Leila Haddad, Oliver Grimm, Christine Esslinger, Dagmar Gass, Daniela Mier and Carina Sauer for research assistance.
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Cao, H., Harneit, A., Walter, H. et al. The 5-HTTLPR Polymorphism Affects Network-Based Functional Connectivity in the Visual-Limbic System in Healthy Adults. Neuropsychopharmacol. 43, 406–414 (2018). https://doi.org/10.1038/npp.2017.121
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DOI: https://doi.org/10.1038/npp.2017.121
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