Neural connectivity as an intermediate phenotype: brain networks under genetic control

Abstract

Recent evidence suggests that default mode connectivity characterizes neural states that account for a sizable proportion of brain activity and energy expenditure, and therefore represent a plausible neural intermediate phenotype. This implies the possibility of genetic control over systems-level connectivity features. Imaging genetics is an approach to combine genetic assessment with multimodal neuroimaging to discover neural systems linked to genetic abnormalities or variation. In the present contribution, we report results obtained from applying this strategy to both structural connectivity and functional connectivity data. Using data for serotonergic (5-HTTLPR, MAO-A) and dopaminergic (DARPP-32) genes as examples, we show that systems-level connectivity networks under genetic control can be identified. Remarkable similarities are observed across modalities and scales of description. Features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure. These data provide convergent evidence for genetic control in humans over connectivity systems, whose characterization has promise for identifying neural systems mediating genetic risk for complex human behavior and psychiatric disease.

Figure 1

Neuroimaging analyses (structure and function) of a common haplotype in PPP1R1B in Caucasian control samples. Top row shows haplotype effects on volume (A) or activation (C, E) in striatum, bottom row shows haplotype effects on structural (B), and functional (D, F) connectivity of striatum with prefrontal cortex. Structural MRI analyses (voxel‐based morphometry): A: significantly reduced volume in striatum (P < 0 05) for carriers of the frequent (CGCACTC) haplotype. B: Greater structural connectivity between prefrontal cortex and striatum for homozygotes for the frequent (CGCACTC) haplotype. Functional imaging analyses (fMRI), n‐back task. C: Significantly reduced reactivity in putamen (P < 0.05) for carriers of the frequent (CGCACTC) haplotype. D: Greater functional connectivity between prefrontal cortex and striatum for homozygotes for the frequent (CGCACTC) haplotype. Functional imaging analyses (fMRI), face matching task. E: Significantly reduced reactivity in striatum (P < 0.05) for carriers of the frequent (CGCACTC) haplotype. F: Greater functional connectivity between prefrontal cortex and striatum for homozygotes for the frequent (CGCACTC) haplotype. t color scales depict statistical significance level (t statistic value) (Reproduced with permission from Meyer‐Lindenberg et al., J Clin Invest, 2007, 117, 672–682 ©American Society for Clinical Investigation). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 2

Serotonergic neurotransmission and associated genetic variants. A: Schematic drawing of serotonergic neuron (Modified with permission from Lesch), showing termination of serotonin (5‐HT) action by the serotonin transporter (5‐HTT) and by catabolism by MAO to 5‐HIAA, as well as synthesis through tryptophane (TRP) and 5‐hyroxytryptophane (5‐HTP). Presynaptic serotonin receptors (1A, B, D, E, F) also shown. B: Schematic drawing of neurodevelopmental effects of increased serotonin level due to inactivation of MAO‐A or 5‐HTT (Modified with permission from Lesch). C: A common variable number of tandem repeat polymorphism in the promoter of the 5‐HTT (5‐HTTLPR) [redrawn from Lesch and Mossner,1998]. A long (L) and short (S) regulatory variant are distinguished, with relatively reduced transcription and activity of the transporter in the S form. D: A common variable number of tandem repeat polymorphism in the promoter of the X‐linked MAO‐A gene affects transcription, with an optimum range (MAOA‐H) of 3.5 or 4 repeats. Redrawn from (Sabol et al.,1998). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 3

Neural mechanisms linked to genetic variation in serotonergic risk genes. (A) Structural (using voxel‐based morphometry) and (B) functional results (during an emotional faces matching task) show an impact of genetic variation in MAO on amygdala and cingulate volume and function (based on data from Meyer‐Lindenberg et al.,2006). Volume is relatively reduced in carriers of the MAOA‐L allele implicated in risk for impulsive violence. Amygdala activation is increased, while activation of regulatory cingulate regions is decreased. (C) Structure and (D) functional connectivity (during a faces matching task) are also affected by genetic variation in 5‐HTTLPR (from Pezawas et al.,2005, with permission). Carriers of the S allele show relative volume reductions in subgenual cingulate and amygdala, and reduced connectivity of amygdala to subgenual cingulate. Reduced connectivity (5‐HTTLPR) or cingulate activation (MAO‐A) predict amygdala hyperactivation by reduced feedback inhibition as an endomechanism underlying anxiety and impulsivity associations of these genes. An anterior medial prefrontal area might modulate this effect (Heinz et al.,2005). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]