Genetic variation inCSMD1affects amygdala connectivity and prosocial behavior

Abstract

The amygdala is one of the most widely connected structures in the primate brain and plays a key role in social and emotional behavior. Here, we present the first genome- wide association study (GWAS) of whole-brain resting-state amygdala networks to discern whether connectivity in these networks could serve as an endophenotype for social behavior. Leveraging published resting-state amygdala networks as a priori endophenotypes in a GWAS meta-analysis of two adolescent cohorts, we identified a common polymorphism on chr.8p23.2 (rs10105357 A/G, MAF (G)=0.35) associated with stronger connectivity in the medial amygdala network (beta=0.20, p=2.97x10-8). This network contains regions that support reward processes and affiliative behavior. People carrying two copies of the minor allele for rs10105357 participate in more prosocial behaviors (t=2.644, p=0.008) and have higher CSMD1 expression in the temporal cortex (t=3.281, p=0.002) than people with one or no copy of the allele. In post-mortem brains across the lifespan, we found that CSMD1 expression is relatively high in the amygdala (2.79 fold higher than white matter, p=1.80x10-29), particularly so for nuclei in the medial amygdala, reaching a maximum in later stages of development. Amygdala network endophenotyping has the potential to accelerate genetic discovery in disorders of social function, such as autism, in which CSMD1 may serve as a diagnostic and therapeutic target.

Evidence for a Pathogenic Role of CSMD1 in Childhood Apraxia of Speech

“…CSMD1 variants are associated with immediate episodic memory and cognitive functions 14 and CSMD1 expression is high in the amygdala, thus affecting social behavior. 16 Moreover, the fact that during early development, neuronal connections between the amygdala and the language processing centers are strengthened in the brain, highlights the role of the amygdala in language learning processes and also the probably potential involvement of CSMD1 in speech impairment.…”

The Diverse Role of CUB and Sushi Multiple Domains 1 (CSMD1) in Human Diseases

“…Athanasiu et al (2017) demonstrated that CSMD1 variants are associated with immediate episodic memory and cognitive function [ 22 ]. Along with a GWAS study, it suggested that CSMD1 is expressed significantly in the amygdala, which affects social behaviour, and CSMD1 can be used as a diagnostic marker for amygdala-related disorders [ 53 ].…”

Frontoamygdala hyperconnectivity predicts affective dysregulation in adolescent moderate-severe TBI

“…We previously defined three anatomically distinct amygdala networks using resting-state fMRI connectivity (rFC) in healthy individuals ( 38 ). These networks support distinct aspects of affective behavior ( 38 , 39 ), serve as endophenotypes for genetic drivers of such behaviors ( 40 ), and degenerate in relation to distinct affective symptoms in frontotemporal dementia ( 41 ). This framework includes a network supporting the perception of salient stimuli containing sensory association regions (yellow), a network supporting the regulation of approach behavior and autonomic activity containing goal- and reward-related regions (red), and a network supporting avoidance learning and behavior containing threat- and pain-responsive regions (blue).…”