Abstract
Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied 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 connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed 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 hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (p FWE = .037), resting‐state fMRI (p FWE = .022), and diffusion tensor imaging (p FWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (p FWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.
Highlights
Human impulsive and aggressive behaviors are determined by multiple causes involving complex interactions between genetic and environmental risk factors, such as Monoamine Oxidase A (MAOA) genotype and early life events (Byrd & Manuck, 2014; Caspi et al, 2002)
We aimed to extend the current understanding of the neurogenetic risk architecture of brain circuits underlying impulsivity and aggression using multimodal neuroimaging and whole-brain connectomic methods in healthy humans stratified by MAOA genotype
From the affected long-range integrative links, nearly half (47%) functionally coupled the frontal cortex to the temporal lobe and subcortical regions. This finding is in line with the established view that MAOA-L mainly impacts prefrontal circuits with a top-down regulatory influence on subordinate neural regions generating evolutionarily conserved physiological responses (Dorfman, Meyer-Lindenberg, & Buckholtz, 2014)
Summary
Human impulsive and aggressive behaviors are determined by multiple causes involving complex interactions between genetic and environmental risk factors, such as Monoamine Oxidase A (MAOA) genotype and early life events (Byrd & Manuck, 2014; Caspi et al, 2002). Functional connectivity analyses revealed increased coupling between amygdala and higher order areas in the ventromedial prefrontal (Buckholtz et al, 2008) and anterior cingulate (Denson, Dobson-Stone, Ronay, von Hippel, & Schira, 2014) cortices (Denson et al, 2014) in MAOA-L carriers. Together, these data suggest that the low-activity allele of MAOA facilitates alterations in cortico-limbic circuits critical for negative emotion regulation and inhibitory control, likely through excessive serotonergic signaling during vulnerable periods of brain development (Cases et al, 1995). Most imaging genetics studies on MAOA focused on specific brain functional domains, a limited set of neural regions and/or a single neuroimaging data modality, making a more comprehensive understanding of the neural connectomic effects difficult (Klein, van Donkelaar, Verhoef, & Franke, 2017)
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