Introduction
Schizophrenia (SCZ) and bipolar disorder (BPD), widely recognized as
highly debilitating hereditary mental illnesses, affect an estimated 2%
of the Canadian population \citep{Dobson2020}. 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 \citep{McCormick2015}. On the contrary,
SCZ patients suffer an array of symptoms that are classified as
positive, negative, and cognitive. According to \citet{Frith2000},
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 \citep{Chatterton2008}.
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 (\citealt{Goeree2005}; \citealt{Stimmel2004}). The lifetime risk of
suicide is 170 and 30 times higher than the general population for BPD
and SCZ, respectively (\citealt{Dome2019}; \citealt{Zaheer2020}). 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
\citep*{Lasebikan2013}.
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 \citep{McIntosh2005}. A
growing body of research around potential genetic underpinnings supports
that variations in the same genes influence how susceptible people are
to both conditions \citep{Craddock2005}. 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 \citep*{Calejo2015}. 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 \citep{Huang1997}.
A recent exome–sequencing study by \citet{Palmer2022} 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
\citep{Sanders2019}. 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.