Functional consequences of calmodulin variants identified among schizophrenia patients and controls

Calmodulin is a vital cellular calcium sensor expressed by the genes CALM1-3. Ultra-rare loss-of-function missense variants in the C-terminal lobe (C-lobe) of calmodulin are linked to cardiac arrhythmia, primarily long QT syndrome. Emerging evidence suggests calmodulin variants also contribute to neurological disorders. This study explores the allelic spectrum and functional consequences of calmodulin variants in schizophrenia. In a large-scale sequencing effort involving 24,248 schizophrenia patients and 97,322 control individuals, 25 unique calmodulin variants were found in 27 carriers, all ultra-rare. Seven carriers were schizophrenia patients, and 20 were controls. All patient variants affected the C-lobe, while only five of 20 control variants were in the C-lobe, linking C-lobe variants to increased schizophrenia risk. Functional analyses identified two variant classes in patients: Loss-of-function variants, reducing calcium affinity and impairing Ca_V1.2 interaction, and gain-of-function variants, enhancing calcium affinity without affecting Ca_V1.2 gating. Together, this study suggests that consequences of calmodulin variants include increased schizophrenia risk.