Materials and Methods Used

This study was conducted using the PubMed database on articles published
before November 17, 2017 and after 2000. (PubMed is a huge, reliable, and highly
authoritative resource supporting the search and retrieval of biomedical and life
sciences literature with the aim of improving health – both globally and
personally)
Separate searches were made for genes, SNPs and Mutations by using:
Uniport (provides an up-to-date, comprehensive body of protein information),
SNPedia (a site that serves as a database of single nucleotide polymorphisms)
DisGenet (a database which integrates information of human gene-disease
associations (GDAs) and variant-disease associations (VDAs)) and Psychiatric
Genomics Consortium (PGC) (provides summary statistics from its genomic
analyses in order to increase our knowledge of the fundamental basis of major
psychiatric disorders.).

Genetic of Bipolar Disorder

Very little is known for certain about the genetics of bipolar disorder.
Studies suggest that variations in many genes, each with a small effect, may
combine to increase the risk of developing the condition. However, most of these
genetic variations have been identified in single studies, and subsequent research
has not verified them. It is unclear what contribution each of these changes
makes to disease risk. Some of the genetic changes associated with bipolar
disorder have also been found in people with other common mental health
disorders, such as schizophrenia. Understanding the genetics of bipolar disorder
and other forms of mental illness is an active area of research.

Studies suggest that epigenetic factors (It is the study of how your
behaviors and environment can cause changes that affect the way your genes
work) also contribute to a person's risk of developing bipolar disorder. Stressful
events in a person's life, such as a death in the family, can trigger disease
symptoms. Substance abuse and traumatic head injuries have also been
associated with bipolar disorder. It seems likely that environmental conditions
interact with genetic factors to determine the overall risk of developing this
disease.
Result and Findings:
Fifty-five different mutations have been described in 30 research papers by
different genetic analyses including recent WGS analysis. Many of these studies
have led to the discovery of the most probable susceptibility genes for BD,
including ANK3, CACNA1C, NCAN, ODZ4, SYNE1, and TRANK1 (Which will be
tackled later). Exploration has started the role of several of these mutations in BD
pathophysiology using in vitro (a complex series of procedures used to help with
fertility or prevent genetic problems and assist with the conception of a child) and
animal models.
These extensive data, crossed with the clinical parameters for BD, report a
set of possible candidates linked to six different genes, some of which have also
been investigated by amygdala activity studies or in vitro models reporting a
possible physiopathological role of these variants and bipolar disorder. The
majority of these SNPs are gene variants located in no-coding regions (This
corresponds to the portions of an organism's genome that do not code for amino
acids, the building blocks of proteins, such as in the intronic gene section)

MAIN GENES AND MUTATIONS DESCRIBED IN BIPOLAR DISORDERS

Locus Gene name SNP Risk Allele Odds Ratio
10q21.2 ANK3 rs1094415 C 1.27
12p13.33 CACNA1C rs1006737 A 1.14
rs2159100 T 1.18
11q14 ODZ4 rs12576775 A 0.85 – 1.10
rs17138171 C
19p13.11 NCAN rs1064395 A 1.17
6q25 SYNE1 rs9371601 T 1.14
3p22 TRANK1 rs9834970 C 1.18

Locus, as we all know, is the location or position of the specific gene on a

chromosome.
 SNP or the Single nucleotide polymorphisms, as mentioned, Each SNP
represents a difference in a single DNA building block, called a nucleotide. So the
rs, stands for Reference SNP plus the cluster ID number is a label used by
researchers and databases like the PubMed to identify a specific SNP. In short, it
is the naming convention used for most SNPs.
And of course, we have the risk alleles. This is the allele that confers a risk
of developing the disease, illness or a disorder.
And lastly, the Odds ratio. This refers to the probability of the individual
carrying a specific disease-associated mutation, or of being affected with a
specific genetic disorder.
ANK3 (Ankyrin-G)
 The allele C in rs10994415 resulted as being associated with BD
which showed an odds ratio equal to 1.27 according in WGS studies
 It has been hypothesized that a potential reason is that variation in
ANK3 may result in dysregulation of sodium ion channels, which may
increase excitatory signalling in the brain and affect mood regulation.
However, the actual contribution of ANK3 is very small, and ANK3 is
only one of many susceptibility genes.

CACNA1C
 The allele A in rs 1006737 and the allele T in rs2159100 are the most
studied SNPs variations and are identified as a genetic risk variant for
bipolar disorder with an odds ratio of 1.14 and 1.18 respectively.
 CACNA1C plays a critical role in neurotransmission, gene expression,
synaptic plasticity, and memory processes in the brain. While
CACNA1C has been studied as a potential disease marker, not only
for bipolar disorder but also for schizophrenia (SCZ), and major
depressive disorder (MDD), there is no concrete evidence to
associate genetic variation in CACNA1C with psychiatric medication
response.

ODZ4
  The hot spot mutation described for BD (and other psychiatric
disorders) are the variants rs12576775 with the allele A and
rs17138171 with the allele C. Odds ratio of, 0.85 - 1.10.
 ODZ4 appears to play a central role in the regulation of neuronal and
synaptic connectivity during brain development. However,
knowledge about ODZ4 is still very limited, and more functional
studies are clearly needed before clinical applications could be
considered.

NCAN
 Recent studies have provided strong evidence that variation in the
gene neurocan (NCAN, rs1064395) is a common risk factor for bipolar
disorder (BD) and schizophrenia.
 However, the possible relevance of NCAN variation to disease
mechanisms in the human brain has not yet been explored.
SYNE1
 The SNP rs9371601 described in the intergenic gene region is
associated to BP with an odds ratio of 1.14.
 The human SYNE1 gene contains 145 exons and encodes multiple
proteins. A recent study has investigated one of its proteins, CPG2.
CPG2 is brain-specific and primarily locates in the excitatory
postsynaptic areas to exert impact on synaptic plasticity and
function. It has been found that the protein expression of CPG2 was
significantly decreased in the post-mortem brains of BPD cases as
compared to control subjects.
TRANK1
 Main studied SNP is rs9834970 which is located about 12 kb distal to
the 3' UTR of TRANK1 (hg18). This variant resulted significant at the P
= 2.4 × 10−11 level, with no heterogeneity.
 Also called LBA1, encodes for a TPR (Translocated Promoter Region, a
protein coding gene) and ankyrin repeat-containing protein, and was
originally identified as a brain-specific antigen in a murine model of
 systemic lupus erythematosus, a human disorder with frequent
neuropsychiatric symptoms.

There are also 4 more other genic candidates:

ADCY2
 The SNPs rs13166360 located in an exonic region are associated in
the literature with BD.
 Which encodes for an integral membrane signalling enzyme
(Adenylate cyclase) involved in the production of cAMP that activates
the Protein Kinase A (PKA) pathways that lead to changes in cellular
metabolism and gene transcription patterns.
GSK3B
 A gene encoded for a glycogen synthase kinase 3 beta.
CUX2 and FAM109A
 The role of two SNPs (rs3847953 and rs933399) positioned in the
chromosome 12 on the genes CUX2 and FAM109 respectively.
Unfortunately, these four demonstrates a lack of information and are described
on a different studies.