Everything you are going to need is in the attachment with all the instructions and dont forget to do as it asks. Its article I need
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
1 2 3 4 5 6 7 8 9 0 () ;, :
12 34 56 78 90 () ;,:
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
Ta b le
1 G en et ic
lo ci
as so ci at ed
w it h B D .
L o cu s
L ea d S N P (s )
M ap p ed
g en es
eQ T L g en es
R ef er en ce s
1 p 3 1 .1
rs 4 6 5 0 6 0 8
N o n e
IF I4 4 L
C h en
et al . [7 6 ]
1 q 2 1 .2
rs 7 5 4 4 1 4 5
O T U D 7 B , R N U 2 -1 7 P
A N P 3 2 E , M R P S 2 1 , P L E K H O 1 , H IS T 2 H 2 A A 3 ,
H IS T 2 H 2 A A 3 , F C G R 1 A , R P R D 2 , S E M A 6 C , V P S 4 5 , S V 2 A ,
H O R M A D 1 , C T S S , A P H 1 A
S ta h l et
al . [8 7 ]
2 q 1 1 .2
rs 2 2 7 1 8 9 3 , rs 5 6 3 6 1 2 4 9 ,
rs 5 7 1 9 5 2 3 9
M IR 3 1 2 7
A R ID
5 A , L M A N 2 L , C N N M 4 , A C T R 1 B
C h en
et al . [7 6 ], C h ar n ey
et al . [1 9 6 ],
S ta h l et
al . [8 7 ]
2 q 2 4 .3
rs 1 7 1 8 3 8 1 4
S C N 2 A , C S R N P 3 , G A L N T 3
N o n e
S ta h l et
al . [8 7 ]
2 q 3 2 .3
rs 6 1 3 3 2 9 8 3
N o n e
N o n e
S ta h l et
al . [8 7 ]
3 p 2 1 .1 -2
rs 2 2 5 1 2 1 9 , rs 2 3 0 2 4 1 7 ,
rs 7 6 1 8 9 1 5
T L R 9 , M IR L E T 7 G , D N A H 1
P C B P 4 , A L A S 1 , T W F 2 , L O C 1 0 1 9 2 9 0 5 4 , P P M 1 M , W D R 8 2 ,
G L Y C T K , M IR 1 3 5 A 1 , T N N C 1 , N IS C H , S T A B 1 , N T 5 D C 2 ,
P B R M 1 , G N L 3 , G L T 8 D 1 , S P C S 1 , N E K 4 , IT IH
1 , IT IH
3 ,
IT IH
4 , IT IH
4 -A S 1 , M U S T N 1 , T M E M 1 1 0 -M
U S T N 1 ,
T M E M 1 1 0 , B A P 1 , P H F 7 , S M IM
4 , R N U 6 -8 5 6 P ,
R N U 6 A T A C 1 6 P , S N O R D 1 9 B , S N O R D 1 9 , S N O R D 6 9
M cM
ah o n et
al . [2 2 6 ], C h en
et al . [7 6 ],
C h ar n ey
et al . [1 9 6 ], S ta h l et
al . [8 7 ]
3 p 2 2 .2
rs 6 5 5 0 4 3 5 , rs 9 8 3 4 9 7 0
D C L K 3 , T R A N K 1
T R A N K 1 , R N U 6 A T A C 4 P , M L H 1 , L R R F IP 2 , G O L G A 4
C h en
et al . [7 6 ], M ü h le is en
et al . [7 7 ],
H o u et al . [7 8 ], C h ar n ey
et al . [1 9 6 ], Ik ed a
et al . [7 5 ], S ta h l et
al . [8 7 ]
3 q 1 3 .1 2
rs 3 8 0 4 6 4 0
L IN C 0 1 2 1 5
C D 4 7 , IF T 5 7
S ta h l et
al . [8 7 ]
4 q 3 2 .2
rs 1 1 7 2 4 1 1 6
F S T L 5
S ta h l et
al . [8 7 ]
5 p 1 5 .3 1
rs 1 4 8 5 3 8 3 9 5 , rs 1 7 8 2 6 8 1 6
A D C Y 2
M ü h le is en
et al . [7 7 ], S ta h l et
al . [8 7 ]
5 q 1 4 .1
rs 1 0 0 3 5 2 9 1
S S B P 2
S ta h l et
al . [8 7 ]
6 q 1 3
rs 5 7 9 7 0 3 6 0
N o n e
N o n e
S ta h l et
al . [8 7 ]
6 q 1 5
rs 1 2 2 0 1 6 7 6
R N G T T , P N R C 1 , P M 2 0 D 2
W an g et
al . [2 2 7 ]
6 q 1 6 .1
rs 1 2 2 0 2 9 6 9 , rs 1 4 8 7 4 4 1 ,
rs 2 3 8 8 3 3 4
L O C 1 0 1 9 2 7 3 1 4
M ü h le is en
et al .[ 7 7 ], H o u et al .[ 7 8 ], S ta h l
et al . [8 7 ]
6 q 2 1
rs 6 5 6 8 6 8 6
M F S D 4 B , R E V 3 L , T R A F 3 IP 2 -A S 1 , T R A F 3 IP 2 , F Y N
F ab b ri et
al . [2 2 8 ]
6 q 2 5 .2
rs 1 2 0 3 2 3 3
S Y N E 1 , S Y N E 1 -A S 1 , R N A 5 S P 2 2 3
G re en
et al . [2 2 9 ], C h ar n ey
et al . [1 9 6 ]
6 q 2 7
rs 1 0 3 9 0 0 2 , rs 1 0 4 5 5 9 7 9
P D E 1 0 A , R P S 6 K A 2
K er n er
et al . [2 3 0 ], S ta h l et
al . [8 7 ]
7 p 2 1 .3
rs 1 1 3 7 7 9 0 8 4
T H S D 7 A , L O C 1 0 2 7 2 5 1 9 1
S ta h l et
al . [8 7 ]
7 p 2 2 .3
rs 4 2 3 6 2 7 4 , rs 4 3 3 2 0 3 7
M IR 4 6 5 5
M A D 1 L 1 , M R M 2 , E L F N 1
H o u et
al . [7 8 ], Ik ed a et
al . [7 5 ]
7 q 2 2 .3
rs 7 3 1 8 8 3 2 1
S R P K 2 , P U S 7
S ta h l et
al . [8 7 ]
7 q 3 4
rs 1 4 2 6 7 3 0 9 0
S ta h l et
al . [8 7 ]
9 p 2 1 .3
rs 1 2 5 5 3 3 2 4
H o u et
al . [7 8 ]
9 q 3 2
rs 1 0 5 1 3 2 4 9
W H R N
F ab b ri et
al . [2 2 8 ], B au m
et al . [7 9 ]
9 q 3 3 .1
rs 1 1 7 8 9 3 9 9
W an g et
al . [2 2 7 ]
The genetics of bipolar disorder 547
Ta b le
1 (c o n ti n u ed )
L o cu s
L ea d S N P (s )
M ap p ed
g en es
eQ T L g en es
R ef er en ce s
1 0 q 2 1 .2
rs 1 0 9 9 4 2 9 9 , rs 1 0 9 9 4 3 1 8 ,
rs 1 0 9 9 4 3 3 6 , rs 1 0 9 9 4 4 1 5 ,
rs 4 9 4 8 4 1 8
A N K 3
F er re ir a et
al . [7 3 ], C h en
et al . [7 6 ],
M ü h le is en
et al . [7 7 ], C h ar n ey
et al . [1 9 6 ],
S ta h l et
al . [8 7 ]
1 0 q 2 5 .1
rs 1 0 8 8 4 9 2 0 , rs 5 9 1 3 4 4 4 9
S O R C S 1 , M X I1 , S M N D C 1
X P N P E P 1 , A D D 3
C h ar n ey
et al . [1 9 6 ], S ta h l et
al . [8 7 ]
1 1 p 1 5 .4
rs 6 4 8 4 2 1 8
A M P D 3
H u an g et
al . [1 8 3 ]
1 1 q 1 2 .2
rs 1 2 2 2 6 8 7 7 , rs 1 7 4 5 7 6 , rs 2 8 4 5 6
D K F Z P 4 3 4 K 0 2 8 , M Y R F , T M E M 2 5 8 , M IR 6 1 1 , F E N 1 ,
F A D S 2 , F A D S 1 , M IR 1 9 0 8 , F A D S 3 , B E S T 1 , L O C 1 0 0 5 0 7 5 2 1
Ik ed a et
al . [7 5 ], S ta h l et
al . [8 7 ]
1 1 q 1 3 .2
rs 1 0 8 9 6 0 9 0
C A T S P E R 1 , G A L 3 S T 3 , T M E M 1 5 1 A
C S T 6 , S N X 3 2 , P E L I3 , E IF 1 A D , C T S W , F IB P , R N A S E H 2 C ,
B A N F 1 , S F 3 B 2 , C N IH
2 , R A B 1 B , Y IF 1 A , P A C S 1 , K L C 2
S ta h l et
al . [8 7 ]
1 1 q 1 3 .2
rs 7 1 2 2 5 3 9
C S T 6 , B B S 1 , B B S 1 , Z D H H C 2 4 , B 4 G A T 1 , S P T B N 2 ,
C 1 1 o rf 8 0 , C C D C 8 7 , C C S , L O C 1 0 2 7 2 4 0 6 4 , C T S F , R C E 1 ,
P C , L R F N 4
S ta h l et
al . [8 7 ]
1 1 q 1 3 .4
rs 1 2 5 7 5 6 8 5
S H A N K 2
S ta h l et
al . [8 7 ]
1 1 q 1 4 .1
rs 1 2 2 9 0 8 1 1 , rs 1 2 5 7 6 7 7 5
T E N M 4 (O
D Z 4 ), M IR 7 0 8
S k la r et
al . [7 4 ], M ü h le is en
et al . [7 7 ],
Ik ed a et
al . [7 5 ]
1 2 p 1 3 .3 3
rs 1 0 7 4 4 5 6 0 , rs 4 7 6 5 9 1 3
C A C N A 1 C -I T 1 , C A C N A 1 C -I T 2 ,
C A C N A 1 C -A
S 4 , C A C N A 1 C -I T 3 ,
C A C N A 1 C -A
S 3
C A C N A 1 C
S k la r et al .[ 7 4 ], C h ar n ey
et al .[ 1 9 6 ], S ta h l
et al . [8 7 ]
1 2 q 1 3 .1 2
rs 1 0 4 5 9 2 2 1 , rs 1 0 5 4 4 4 2
K M T 2 D , R H E B L 1 , D H H
W N T 1 0 B , C A C N B 3 , C C D C 6 5 , F K B P 1 1 , A R F 3 ,
L O C 1 0 5 3 6 9 7 5 8 , D D N , P R K A G 1 , L M B R 1 L , T U B A 1 B
H o u et
al . [7 8 ], C h ar n ey
et al . [1 9 6 ]
1 3 q 1 4 .1 1
rs 1 0 1 2 0 5 3
D G K H
B au m
et al . [7 9 ]
1 5 q 1 5 .2
rs 4 4 4 7 3 9 8
G A N C , C A P N 3 , S N A P 2 3 , L R R C 5 7 , H A U S 2 , S T A R D 9 ,
T T B K 2 , A D A L
S ta h l et
al . [8 7 ]
1 5 q 2 5 .3
rs 1 3 9 2 2 1 2 5 6
S ta h l et
al . [8 7 ]
1 6 p 1 2 .2
rs 4 2 0 2 5 9
C O G 7 , G G A 2 , E A R S 2 , P A L B 2 , D C T N 5 , P L K 1 , E R N 2
B u rt o n et
al . [7 1 ], Ji an g et
al . [2 3 1 ]
1 6 p 1 3 .2
rs 1 1 6 4 7 4 4 5
G R IN
2 A
S ta h l et
al . [8 7 ]
1 7 q 1 2
rs 2 5 1 7 9 5 9
M IR 4 7 2 8 , M IE N 1 , G R B 7
T C A P , Z P B P 2 , G S D M A , M E D 1 , S T A R D 3 , IK
Z F 3 ,
O R M D L 3 , P N M T , P P P 1 R 1 B , P G A P 3 , E R B B 2 , G S D M B
H o u et
al . [7 8 ]
1 7 q 2 1 .3 1
rs 1 1 2 1 1 4 7 6 4
L O C 1 0 5 3 7 1 7 8 9 , R N U 6 -1 3 1 P , T M U B 2 ,
A T X N 7 L 3
T M E M 1 0 1 , S L C 2 5 A 3 9 , R N U 3 P 1 , M P P 2 , U B T F , G 6 P C 3 ,
H D A C 5 , C 1 7 o rf 5 3 , A S B 1 6 , A S B 1 6 -A
S 1
S ta h l et
al . [8 7 ]
1 8 q 2 1 .3 3
rs 1 1 5 5 7 7 1 3
Z C C H C 2
S ta h l et
al . [8 7 ]
1 9 p 1 3 .1 1
rs 1 0 6 4 3 9 5 , rs 1 1 1 4 4 4 4 0 7
N C A N , R N U 6 -1 0 2 8 P , M IR 6 4 0
R F X A N K , G M IP , Z N F 5 0 6 , Z N F 1 0 1 , A T P 1 3 A 1 , B O R C S 8 –
M E F 2 B , B O R C S 8 , N D U F A 1 3 , T S S K 6 , T M 6 S F 2 , Y JE F N 3 ,
M A U 2 , G A T A D 2 A , C IL P 2 , L P A R 2 , H A P L N 4 , S U G P 1
C ic h o n et
al . [2 3 2 ], S ta h l et
al . [8 7 ]
1 9 p 1 3 .1 3
rs 4 9 2 6 2 9 8
N F IX
D N A S E 2 , P R D X 2 , G C D H , S Y C E 2
Ik ed a et
al . [7 5 ]
2 0 q 1 3 .1 2
rs 6 1 3 0 7 6 4 , rs 6 7 7 1 2 8 5 5
W F D C 5 , R B P JL
S T K 4 -A
S 1 , M A T N 4 , D N T T IP 1 , T N N C 2 , S Y S 1 , T P 5 3 T G 5 ,
S L P I, W F D C 1 2 , S E M G 1 , Y W H A B , P A B P C 1 L , S T K 4 ,
K C N S 1 , P I3
S ta h l et
al . [8 7 ]
eQ T L g en es
re fe r to
g en es
w h o se
ex p re ss io n is as so ci at ed
w it h a S N P th at
is in
li n k ag e d is eq u il ib ri u m
w it h th e le ad
S N P (s )
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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 r
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