Imaging Genetics Approaches to Identify Mechanisms in Severe Mental Illness

Abstract

Schizophrenia, bipolar disorder, and major depressive disorders are heritable serious mental illnesses (SMI). What does this heritability mean? What are the underlying mechanisms? Large genome-wide association studies (GWAS) have identified both shared and unique genetic risk variants for these disorders; however, causal risk variants, their molecular mechanisms, and their effects on brain circuitry are mostly unknown. Targeted, possibly individualized, therapies addressing underlying mechanisms offer the promise of improved functioning and well-being for patients. The study of the effects of the CACNA1C gene on episodic memory-associated neural circuitry by Erk et al. (1) provides a noteworthy use of the imaging-genetics approach to aid in our understanding of biological mechanisms underlying SMI. Typically, the imaging-genetics approach refers to the use of structural or functional imaging data to evaluate genetic variation or more infrequently, the use of imaging data to discover genes related to disorders or symptoms. The rs1006737 A allele is a risk factor for bipolar disorder, major depressive disorder, and schizophrenia in large GWAS, making the CACNA1C gene an important therapeutic target. The rs1006737 A allele itself may not be the causal variant but may merely “tag” the true causal DNA variants. These causal variants tagged by the rs1006737 single nucleotide polymorphism (SNP) may or may not be identical among individuals, both within and across disorders. This can be resolved by DNA sequencing. Additionally, gene function is frequently modified by other factors including other genes (e.g., epistasis), methylation (epigenetics), or copy number variations or transposable element changes in DNA structure (2). Genetic variation can cause dysfunction in the CACNA1C (also called Cav1.2), which encodes the alpha-1 subunit protein of a longterm (L)-type voltage-dependent calcium channel that mediates calcium ion influx. The calcium channel consists of alpha-1, alpha-2/ delta, and beta subunits in a 1:1:1 ratio. Inactivation of the CACNA1C gene produces profound memory effects in mice. Electrophysiological, biochemical, and behavioral analyses of mice lacking the Cav1.2 gene strongly support the role for L-type voltage calciumdependent function in hippocampus-based learning and memory (3). The influx of calcium through these channels triggers hippocampus-dependent synaptic plasticity associated with memory. Interestingly, this effect on long-term potentiation appears to be N-methyl-D-aspartate-independent, in contrast to other long-term potentiation mechanisms. L-type calcium channel blockers such as nimodipine and verapamil both bind to these calcium channels and have some demonstrated efficacy in treating bipolar disorder and schizoaffective disorder. Incidentally long QT syndrome, as well as QTc (a measure of time between the beginning of the Q wave and beginning of the T wave in the heart's electrical cycle, corrected