Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects

Abstract Calmodulin acts as a vital calcium sensor in cells, crucial for relaying calcium signals to different protein partners. While rare missense variants in calmodulin are linked to cardiac arrhythmia, particularly long QT syndrome (LQTS), their role in schizophrenia remains unexplored. We investigated missense variants in the calmodulin-encoding genes CALM1-3 in a large-scale sequencing effort involving 24,248 schizophrenia patients and 97,322 controls. Seven carriers were found among cases and twenty among controls. Notably, all schizophrenia variants affected the C-terminal lobe of the protein, compared to only five in controls, linking calmodulin C-lobe missense variants and schizophrenia risk (odds ratio 5.62, P =0.043). Functional analyses revealed two classes of calmodulin variants in schizophrenia: 1) loss-of-function variants that reduce calcium affinity and impair the interaction with voltage-gated calcium channel 1.2 (Ca V 1.2), akin to LQTS variants but with smaller effect size, and 2) gain-of-function variants that unexpectedly enhance calcium affinity with no impact on Ca V 1.2 gating. This study for the first time statistically and functionally links calmodulin missense variants to a neurological disorder, expanding the phenotypic spectrum of calmodulinopathies to include schizophrenia. Significance Neurons use calmodulin to monitor calcium signals and modulate hundreds of target proteins, thereby regulating key processes such as neuronal firing and memory and learning. Here, we link genetic variants in calmodulin to schizophrenia risk. Moreover, these genetic variants have divergent consequences for calmodulin protein function. Our results expand the current understanding of calmodulin variants, which are primarily reported in cardiac arrhythmia patients, and generally have a strong loss-of-function effect on the protein. We here provide the first identification and characterization of calmodulin variants in non-cardiac patients. This broadens our view of the physiological and functional consequences of human calmodulin variants and presents novel mechanistic entries to understanding the molecular mechanisms of schizophrenia.