Genetic variation in CSMD1 affects amygdala connectivity and prosocial behavior

Bickart, K. C.; Napolioni, V.; Khan, R. R.; Kim, Y.; Altmann, A.; Richiardi, J.; Newsom, M.; Sadaghiani, S.; Banaschewski, T.; Bokde, A. L.; Quinlan, E. B.; Desrivieres, S.; Flor, H.; Garavan, H.; Gowland, P.; Heinz, A.; Ittermann, B.; Martinot, J.-L.; Paillere Martinot, M.-L.; Artiges, E.; Nees, F.; Papadopoulos Orfanos, D.; Paus, T.; Poustka, L.; Froehner, J. H.; Smolka, M. N.; Walter, H.; Whelan, R.; Schumann, G.; Ng, B.; Greicius, M. D.; Consortium, I.

doi:10.1101/2020.09.27.315622

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bioRxiv · 10.1101/2020.09.27.315622

Genetic variation in CSMD1 affects amygdala connectivity and prosocial behavior

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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.

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Bickart, K. C., Napolioni, V., Khan, R. R., Kim, Y., Altmann, A., Richiardi, J., Newsom, M., Sadaghiani, S., Banaschewski, T., Bokde, A. L., Quinlan, E. B., Desrivieres, S., Flor, H., Garavan, H., Gowland, P., Heinz, A., Ittermann, B., Martinot, J.-L., Paillere Martinot, M.-L., Artiges, E., Nees, F., Papadopoulos Orfanos, D., Paus, T., Poustka, L., Froehner, J. H., Smolka, M. N., Walter, H., Whelan, R., Schumann, G., Ng, B., Greicius, M. D., Consortium, I.. 2020-09-27. Genetic variation in CSMD1 affects amygdala connectivity and prosocial behavior. https://doi.org/10.1101/2020.09.27.315622

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