+1443 776-2705 panelessays@gmail.com
  

  

Everything you are going to need is in the attachment with all the instructions and don’t forget to do as it asks. Its article I need one slides PowerPoint. Please just need one slide on part “G-Discuss your conclusion”. I need one slide and a side note to explain the slide in detail with references. 

RN326 Mental Health, July 2021 Session

RUA Group PPT Presentation

Each group will prepare a Power Point (PPT) Presentation utilizing Scholarly Nursing Research/Journal Articles that have been approved by the Faculty (See Course Calendar for due date and Presentation date)

Please submit your articles via permalink attachment if the article is from Chamberlain library

for approval

prior to developing your PowerPoint.

If the article is not from Chamberlain Library, download the article and send it via email attachment for approval [DO NOT SUBMIT LINK, COPY AND PASTE IS NOT ACCEPTED].

Note that you will be presenting to a Focus Group that need to learn about the disorder. Each group will utilize information collected from the Scholarly Articles to develop the Power Point Presentation. Additional resources may be used. Your Course Textbook must be used as one of your resources/references.

Discuss the following in your Presentation/PPT:

· A brief introduction of your assigned disorders

· A brief introduction of the scholarly article’s topic and explain why it is important to mental health nursing.

· b. Cite statistics to support the significance of the topic.

· c. Summarize the article; include key points or findings of the article.

· d. Discuss how you could use the information for your practice; give specific examples.

· e. Identify strengths and weaknesses of the article.

· f. Discuss whether you would recommend the article to other colleagues.

· g. Discuss your conclusion.

Include an APA title page [include Group #, your group topic, and names of group member] and a reference page; include in-text citations (use citations whenever paraphrasing, using statistics, or quoting from the article).
Please refer to your APA Manual as a guide for in-text citations and sample references page.
Additionally, include speaker notes in each of your slides.

Each member of the group must participate in the presentation to receive the point.

You can use a
3 x 5 index card
note for your presentation. Do not read from your notes, PPT, or articles during your presentation, the index card only serve as a reference. Reading to your audience from your note or PPT without expanding on the information will cost the group 3% deduction from your total points.

Each student must submit a copy of his/her group PPT in the grade book.

Dress Code: Semi-Business attire or Your Clinical Uniform (If your group decide to wear Clinical Uniform, every member must wear Clinical Uniform, the same apply if your group decide to wear Semi-business attire – i.e. all member must wear semi-business attire).

Grading Rubric: Criteria are met when the student’s application of knowledge demonstrates achievement of the outcomes for this assignment. Please see RUA Guidelines in Canvas.

Points for this Assignment: 50

Molecular Psychiatry (2020) 25:544–559
https://doi.org/10.1038/s41380-019-0634-7

EXPERT REVIEW

The genetics of bipolar disorder

Francis James A. Gordovez1,2 ? Francis J. McMahon 1

Received: 29 April 2019 / Revised: 22 November 2019 / Accepted: 11 December 2019 / Published online: 6 January 2020
This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020

Abstract
Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very
challenging endeavor. Genome-Wide Association Studies (GWAS) have transformed our understanding of BD, providing the
first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of
schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants
together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare
copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other
alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some
clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.

Introduction

The genome-wide association studies (GWAS) era has
transformed our understanding of bipolar disorder (BD). Ten
years ago, BD was considered a distinct, highly heritable
disorder for which genes of major effect had eluded detection
by linkage studies but were expected to be found eventually.
Now, numerous common genetic markers have been found
by GWAS, none of which confers major risk for disease, and
many of which overlap with markers associated with schi-
zophrenia or major depression. A few higher-risk associations
have also been identified, involving rare copy number variants
(CNVs) that are usually not inherited. Now, BD can be
regarded as a point on a spectrum of risk, ranging from major
depression to schizophrenia. Despite this substantial progress,
most of the inherited risk for BD remains unexplained, sug-
gesting that there is still much to learn about the genetics of
BD. In this review, we will summarize the key developments
in BD genetics over the past decade and frame some open
questions that will need to be addressed by future studies

before we can fully realize the promise of “genomic medi-
cine” in the diagnosis and treatment of BD.

The phenotype

Common

BD is among the most common of major mental illnesses,
with prevalence estimates in the range of 1–4% [1]. How-
ever, since the diagnosis rests on reports of subjective
symptoms that can be subtle, diagnosed cases probably
represent the tip of an iceberg of very common disturbances
in mood and behavior that blend imperceptibly into the
clinical realm. Genetic studies have focused almost entirely
on individuals who can be easily diagnosed by interview or
are already in treatment, which undoubtedly provides an
incomplete picture. Imagine trying to describe the genetics
of hypertension by studying only stroke patients.

Varied clinical features

The genetic complexity of BD is belied by its complex and
varied clinical presentation [2]. Although the first episode of
major depression or mania typically begins between ages 18
and 24 [3], earlier or later onset cases are not rare. Episodes
can be frequent or separated by many years, and some
patients experience rapid cycling with a period of hours or
days [4]. Comorbid anxiety [5, 6] and substance abuse [7, 8]
are common, and psychotic features are often a component

* Francis J. McMahon
[email protected]

1 Human Genetics Branch, National Institute of Mental Health
Intramural Research Program, Department of Health and Human
Services, National Institutes of Health, Bethesda, MD, USA

2 College of Medicine, University of the Philippines Manila, 1000
Ermita, Manila, Philippines

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of mood episodes, particularly manias. Interepisode periods
can be completely symptom-free or beset with chronic
depressive or manic symptoms. Some people suffer only
from manias, although this is uncommon [9]. Mixed states
are frequent, as are periods of prolonged, treatment-resistant
depression [2]. With such protean manifestations, it seems
likely that what we now call BD may ultimately be resolved
into dozens of biologically distinguishable disease entities.

Many studies have examined the familiality of clinical
features in BD. Age at onset [10], psychotic symptoms
[11, 12], frequency of manic and depressive episodes [13],
and polarity (mania or depression) at onset [14] are all
highly familial, while comorbid anxiety and substance
abuse are less so [15]. Below we will address some of the
genetic signals that may help explain these patterns.

High risk of suicide

Many studies have pointed to a high risk of suicide in BD
[16–20]. On average, about 15% of people diagnosed with
BD die of suicide [21], a number that has remained dis-
couragingly stable for decades. Several small studies have
reported that suicide may be especially common in some
families with BD [18, 22, 23], suggesting specific genetic
or shared environmental factors, but these have so far
remained elusive.

Cycling as a distinct trait

Signs and symptoms of BD are so wide-ranging that they
can be seen, in part, in just about every major psychiatric
disorder. This makes for challenging differential diagnosis,
one of the reasons that it has proven more difficult to
accumulate very large samples of BD than schizophrenia,
autism, or major depression. The one very distinctive trait
seen in everyone with BD is cycling: episodic elevations
and depressions of mood and behavior, separated by periods
of relative or complete euthymia [4]. This is such a core
feature of BD as currently conceived that we will probably
not consider the genetics of BD to be solved until the
genetic mechanism of cycling itself has been elucidated.

Response to lithium

Another relatively distinctive clinical feature of some peo-
ple with BD is the response to lithium. Indeed about one-
third of people diagnosed with BD will experience a dra-
matic improvement in the frequency and severity of mood
episodes while receiving lithium, and another third with be
at least somewhat improved [24]. Lithium is also the only
drug shown to exert a protective effect against suicide in
BD [17, 19, 20, 25]. No other major mental illness shows
this kind of specific response to lithium, suggesting that

genetic risk factors unique to BD are in some way related to
the pharmacodynamics of lithium and that biologically
meaningful subtypes of BD may be identifiable, at least in
part, by response to lithium therapy. A few GWAS of
lithium response have been published, but the results so far
are divergent [26–29]. Some recent studies using cellular
models lend support to the view that lithium-responsive BD
carries a distinct neurobiological signature [30–32].

Genetic epidemiology

Before the era of molecular genetics, much of our etiologic
understanding of BD rested upon the methods of genetic
epidemiology. Family studies demonstrated that BD runs in
families, with a 10–15% risk of mood disorder among first-
degree relatives of people with BD, but could not distin-
guish the effects of shared environment from those of
shared genes [33]. Twin studies showed that much of the
shared familial risk could indeed be explained by shared
genes, with heritability estimates on the order of 70–90%
[33]. Adoption studies lent further support to a largely
genetic etiology, since BD was elevated only in the biolo-
gical parents of adult adoptees with the illness [33]. Despite
the strong and consistent evidence in favor of a genetic
etiology; however, segregation analyses could not find a
clear, Mendelian pattern of transmission, tending instead to
favor more complex models of inheritance [34].

Assortative mating

Assortative mating refers to nonrandom mating among
individuals in a population [35]. People with similar phe-
notypes may be more likely to mate or may selectively
avoid potential mates with other phenotypes. A number of
studies over the past decades have demonstrated varying
degrees of assortative mating in BD, with an increased rate
of matings between individuals with BD and those with BD,
major depression, alcoholism, or other phenotypes [35–43].
Recent, large population-based studies have found similar
patterns of assortative mating across psychiatric and other
traits, including height [44], activity level [45], emotional
intelligence [46], and educational and social status [47].

Such substantial rates of assortative mating are likely to
have a major impact on the genetic landscape of BD but are
often not considered in studies of the disorder. Theoreti-
cally, assortative mating can lead to accumulation of risk
alleles in subsequent generations, with consequent increases
in rates or severity of illness across generations of a family,
a phenomenon known as anticipation [48]. Assortative
mating across traits can also induce genetic correlations and
comorbidity between the traits in offspring, but these are not
likely to persist in the face of random mating by subsequent

The genetics of bipolar disorder 545

generations [49]. Assortative mating does not appear to
effect heritability estimates by twin studies but may con-
tribute to underestimates of heritability by empirical rela-
tionship methods based on SNP arrays [50]. This is because
individuals drawn from populations with nonrandom mat-
ing will tend to share more risk alleles than would be
expected based on their overall genetic relatedness.

Risk loci

Initial searches for risk loci depended on a very limited set
of genetic methods, chiefly genetic linkage analysis
[14, 51, 52]. However, since linkage methods do not work
well in the face of complex patterns of inheritance, linkage
studies of BD failed to produce definitive, replicable find-
ings [53]. A similar problem faced linkage studies of most
other common, complex traits.

Candidate genes

In an attempt to overcome the limitations of linkage
methods, many researchers tried to find genetic markers that
were chosen on the basis of their proximity to genes that
encoded proteins of known neurobiological importance,
such as the serotonin transporter [54]. Unfortunately, this
candidate gene strategy was largely unsuccessful. This is
because the selection of candidate genes with a high-prior
probability of involvement in BD proved to be quite diffi-
cult. Most candidate gene studies of BD also suffered from
the same biases due to small sample size and undetected
genetic mismatch between cases and controls that bedeviled
other such studies of a variety of common traits [55]. While
meta-analyses do tend to support a small contribution from
at least a few well-studied candidates, including the ser-
otonin transporter, SLC6A4 [56–59], d-amino acid oxidase,
DAOA [58, 60–62], and brain-derived neurotrophic factor
[58, 63–70], the most reliable association evidence has
come from GWAS.

GWAS

Genome-wide association studies, wherein large numbers of
genetic markers spanning the genome are tested for asso-
ciation with a trait, typically in large, case–control samples,
have so far been the most successful strategy for identifying
genetic variants associated with BD. Since the first BD
GWAS appeared in 2007 [71], almost 20 such studies have
been published. Most have focused on typical case defini-
tions of bipolar I disorder [26, 72–83], but some have
examined clinical subtypes such as schizoaffective disorder
[84], bipolar II [85], or BD in the context of personality [86]
or other traits. The most recent published GWAS, based on

~50 K cases, detected 30 genome-wide significant loci, of
which 20 were newly identified [87].

Genome-wide significant loci reported to date are sum-
marized in Table 1. As with most other common traits, risk
loci are numerous, most of the lead SNPs are noncoding,
and odds ratios are small (1.1–1.3). Although many of the
loci have been implicated by several studies, only a few loci
can be resolved to single genes [88, 89] based on current
information, so it is still too early to make firm conclusions
about specific risk genes underlying most GWAS loci. As
functional genomic data accumulates, convergent findings
are expected to point toward specific risk genes and
pathways.

Convergent data so far highlight at least three genes.
ANK3, located on chromosome 10q21.2, was one of the
earliest genes to be implicated in BD by GWAS [72, 90–93].
Significant association has now been found between BD and
SNPs near ANK3 by several studies, and several of those
SNPs affect expression of ANK3 [90, 91, 94–96]. ANK3
encodes ankyrin B, a protein involved in axonal myelina-
tion, with expression in multiple tissues, especially brain
[97]. Numerous alternative transcripts exist, suggesting a
potential role for alternative splicing [98]. A conditional
knock-out mouse displays cyclic changes in behavior that
resemble BD and respond to treatment with lithium [99].
CACNA1C, located on chromosome 12p13, has also been
implicated by genome-wide significant SNP associations in
several studies of BD, along with schizophrenia and major
depression; some of the associated SNPs are also associated
with expression of CACNA1C in multiple tissues, including
brain [73, 74, 87, 100–103]. The gene encodes an L-type
voltage-gated ion channel with well-established roles in
neuronal development and synaptic signaling. Heterozygous
knockdown of the gene in mice alters a variety of behaviors
thought to reflect mood, but without a clear syndromic
resemblance to BD [102]. TRANK1, which resides on
chromosome 3p22, has been implicated by genome-wide
significant association with nearby SNPs in studies of BD
and schizophrenia [75–77, 104, 105]. TRANK1 encodes a
large, mostly uncharacterized protein, highly expressed in
multiple tissues, especially brain, and may play a role in
maintenance of the blood–brain barrier [106]. The expres-
sion of TRANK1 is increased by treatment with the mood
stabilizer valproic acid, and cells carrying the risk allele
show decreased expression of the gene and its protein [104].
Recent transcriptomic studies suggest that DCLK3 may be
another gene in the same 3p22 GWAS locus that contributes
to risk for both BD and schizophrenia [88, 107].

While each individual GWAS “hit” has only a small
effect on risk, polygenic risk scores that combine the
additive effects of many risk alleles (often hundreds or
thousands) can index substantially more genetic risk by
including variants that have so far escaped detection

546 F. J. A. Gordovez, F. J. McMahon

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The genetics of bipolar disorder 547

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w
it
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le
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S
N
P
(s
)

548 F. J. A. Gordovez, F. J. McMahon

individually at genome-wide significance [108]. Recent
studies that use the PRS strategy have shown that common
variation accounts for about 25% of the total genetic risk for
BD (less of the phenotypic variance), that PRS overlap
substantially between BD and schizophrenia, and that PRS
derived from large schizophrenia samples are associated
with increased rates of psychotic symptoms and decreased
response to lithium in BD [101, 105, 109].

Copy number variants (CNVs)

CNVs are stretches of DNA that occur in one (deleted),
three (duplicated) or more copies on a chromosome, rather
than the typical two copies expected in the diploid human
genome. Initially discovered by use of hybridization or SNP
array methods that could detect deletions and duplications
too small to be found reliably by cytogenetic methods, large
(30–1000 kb) CNVs have since been shown to play a major
role in neurodevelopmental disorders [110–116] and some
cases of schizophrenia [110, 117–123].

CNVs seem to play a smaller role in BD [124], but at
least two CNVs have been associated with BD in large,
case–control samples. The 650 kb duplication on chromo-
some 16p11.2 was initially described in a de novo study of
schizophrenia [125] and was later detected as a de novo
event in a proband with early-onset BD [126]. Genome-wide
significant evidence of association with BD is based on a
large meta-analysis of SNP array data, in which the dupli-
cation conferred an OR of 4.37 (95% CI: 2.12–9.00) [127].
This same study also found evidence of association with a
deletion on 3q29, but this fell short of genome-wide sig-
nificance [127]. Both of these CNVs have also been asso-
ciated with schizophrenia, autism, and intellectual disability
[128]. A reciprocal deletion in the 16p11.2 region is asso-
ciated with autism and ID [129, 130]. One recent study
found enrichment of genic CNVs in schizoaffective BD
[131]. Taken together, these findings suggest that the genetic
overlap between BD and schizophrenia extends beyond
common, low-risk alleles to rare alleles of larger effect.

Most published CNV studies to date have relied on
technologies that cannot reliably detect CNVs much below
~30 kb. As WGS and other technologies come to the fore,
we will doubtless find very large numbers of smaller CNVs
in the human genome. Many such smaller CNVs may also
be associated with various neurodevelopmental and adult
psychiatric disorders and may well be found to play an
important role in BD in the future.

Single nucleotide variants (SNVs) and and small
insertions/deletions (indels)

Next-generation sequencing (NGS) technology has enabled
a search for rare single nucleotide and small insertion/

deletion variants that are not represented in SNP arrays
[132, 133]. Such studies may uncover alleles co