Introduction

Schizophrenia (SCZ) and bipolar disorder (BPD), widely recognized as highly debilitating hereditary mental illnesses, affect an estimated 2% of the Canadian population (Dobson et al., 2020). Formerly known as manic­–depressive illness, BPD is a chronic psychiatric disease that encompasses three differentiable forms: bipolar I disorder (characterized by severe manic or depressive episodes), bipolar II disorder (marked distinct by hypomanic episodes with decreased relative severity), and cyclothymic disorder (recurring hypomanic and depressive episodes). Overarching symptoms include volatility in mood, sleep patterns, and concentration (McCormick et al., 2015). On the contrary, SCZ patients suffer an array of symptoms that are classified as positive, negative, and cognitive. According to Frith et al. (2000), positive symptoms describe any change in behaviour or thought, including hallucinations and delusions; negative symptoms cause patients to become apathetic and lethargic; and cognitive symptoms are marked by impairments in attention, working memory, and executive functions. As a result, SCZ patients experience general motor and cognitive impairment which interrupts thought processes, perceptions, and emotional responsiveness (Chatterton et al., 2008).
Although SCZ and BPD vary comparably in symptomatology, they are similar in that both are strongly associated with an increased prevalence of suicide, diagnosis of clinical depression, crime, and premature mortality (Goeree et al., 2005; Stimmel, 2004). The lifetime risk of suicide is 170 and 30 times higher than the general population for BPD and SCZ, respectively (Dome et al., 2019; Zaheer et al., 2020).  Primary caregivers, especially in a home environment, experience a tremendous burden in assisting those diagnosed with SCZ or BPD and are recognized as a high–risk group for developing mental disorders themselves (Lasebikan & Ayinde, 2013).
Genetic linkage between SCZ and BPD was once disregarded due to the seemingly unrelated nature of these two mental diseases. However, novel molecular genetic studies have suggested a connection between these disorders via an intermediate phenotype by evidence of certain endophenotypes, namely white matter density (McIntosh et al., 2005). A growing body of research around potential genetic underpinnings supports that variations in the same genes influence how susceptible people are to both conditions (Craddock et al., 2005). For example, the AKAP11 gene, located on the thirteenth chromosome, has been of particular interest.  The AKAP–11 protein, coded for by the AKAP11 gene, is a part of the protein kinase A family of enzymes, which are tetramers of two catalytic and two regulatory subunits docked at precise intracellular sites (Calejo & Taskén, 2015).  AKAP–11 in particular binds to type II regulatory subunits of protein kinase A to assist in various cellular functions, such as liquid metabolism and glycogen regulation (Huang et al., 1997).
A recent exome–sequencing study by Palmer et al. (2022) finds that an excess of AKAP11 protein­–truncating variants (PTVs) is present in both disorders. PTVs are genetic variants predicted to shorten the coding sequence of genes through a premature termination codon, subsequently influencing the development of neuropsychiatric illnesses (Sanders et al., 2019).  In this study, we apply a methodology in which AKAP11 variants are further investigated to establish a genetic background for the diagnosis of both SCZ and BPD.  We hypothesize that certain AKAP11 variants have a statistically significant effect on the diagnosis of both SCZ and BPD.  Similarly, we hypothesize that high–risk AKAP11 variants will demonstrate a correlation with the observed Canadian diagnosis frequencies between age and sex, further testing the validity of the suggested correlation to AKAP11 using real–world data.
While analyses regarding AKAP11 variants have been conducted before, particularly with respect to genome sequencing, they have yet to be tested in combination with genome annotation data, which places relative weightings on each variant such that the more deleterious ones can be focused on.  Additionally, the current body of literature has yet to compare the results against the true frequencies of SCZ and BPD diagnoses.