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Abstract

Most neuropsychiatric disorders are at least moderately heritable. Two functional can- didate variants affecting monoaminergic neurotransmission are MAOA and 5-HTTLPR. Earlier neuroimaging studies connected genetic variance in these polymorphisms with alterations in brain function and structure mainly in corticolimbic circuits. However, these initial findings have been questioned because of failure to replicate in larger co- horts and lack of clear meta-analytic evidence. Therefore, the current work investigated the following hypotheses: 1) Network phenotypes are more sensitive to the subtle ef- fects of typical genetic risk variants than traditional neuroimaging approaches. 2) Ap- plying a whole-brain, connectomic approach will detect widespread effects. 3) Genetic variance in the serotonergic system impacts structural and functional connectivity pat- terns even without an active task. However, a task that challenges a significant cogni- tive domain might increase sensitivity. 4) Networks showing altered connectivity pat- terns in carriers of serotonergic risk variants are also associated with differences in emotion regulation. Study 1 examined a sample of 223 healthy subjects with an emotional face processing task to re-evaluate the association between 5-HTTLPR and amygdala activation, ex- plore potential network-based functional connectivity phenotypes for associations with 5-HTTLPR, and probe the reliability, behavioral significance and potential structural confounds of the identified network phenotype. The number of risk alleles was signifi- cantly correlated with functional connectivity of a visual-limbic subnetwork (pFWE=0.03). Notably, individuals with lower subnetwork connectivity had significantly higher emotion suppression scores (p=0.01). Study 2 examined healthy individuals and used multimodal neuroimaging (sample size range: 219-284 across modalities) and network-based statistics (NBS) to probe the specificity of MAOA-L-related connec- tomic alterations to cortical-limbic circuits and the emotion processing domain. We as- sessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results re- vealed a distributed network of node links with a significantly increased connectivity in MAOA-L carriers compared to the carriers of the high expression (H) variant. The hy- perconnectivity phenotype primarily consisted of between-lobe network links and showed a pronounced involvement of frontal-temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = 0.037), resting-state fMRI (pFWE =0.022), and diffusion tensor imaging (pFWE=0.044) data. The current work confirmed and extended on earlier re- search linking serotonergic genetic variants with altered neural connectivity. Applying connectomic whole brain approaches confirmed earlier findings showing altered fronto- temporal connectivity in carriers of serotonergic risk variants. This novel, connectomic method showed that serotonergic genetic variance affects large brain networks that include but are not limited to frontotemporal regions. The present work confirmed that connectomic, unbiased methods are more sensitive to the often subtle effects of ge- netic risk polymorphisms. Whereas the effect of 5-HTTLPR was only evident during an emotion processing task, MAOA genotype had an effect on resting state connectivity and during emotion processing in addition to anatomic connectivity. One possible ex- planation for this more general effect of MAOA genotype is that in contrast to the 5- HTTLPR polymorphism which selectively affects serotonergic neurotransmission, MAOA is not only involved in serotonergic neural signaling but catalyzes the metabo- lism of other monoaminergic neurotransmitters including noradrenaline and dopamine.