Editing Bipolar disorder (section)

== Causes ==
The causes of bipolar disorder likely vary between individuals and the exact mechanism underlying the disorder remains unclear.<ref name="Nierenberg2013">{{cite journal |vauthors=Nierenberg AA, Kansky C, Brennan BP, Shelton RC, Perlis R, Iosifescu DV | title = Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development | journal = Aust N Z J Psychiatry | volume = 47 | issue = 1 | pages = 26–42 | date = January 2013 | pmid = 22711881 | doi = 10.1177/0004867412449303 | s2cid = 22983555 }}</ref> Genetic influences are believed to account for 73–93% of the risk of developing the disorder indicating a strong hereditary component.<ref name="Bobo2017"/> The overall [[heritability]] of the [[bipolar spectrum]] has been estimated at 0.71.<ref name="Edvardsen2008">{{cite journal |vauthors=Edvardsen J, Torgersen S, Røysamb E, Lygren S, Skre I, Onstad S, Oien PA | title = Heritability of bipolar spectrum disorders. Unity or heterogeneity? | journal = Journal of Affective Disorders | volume = 106 | issue = 3 | pages = 229–240 | year = 2008 | pmid = 17692389 | doi = 10.1016/j.jad.2007.07.001 }}</ref> [[Twin studies]] have been limited by relatively small sample sizes but have indicated a substantial genetic contribution, as well as environmental influence. For bipolar I disorder, the rate at which [[identical twin]]s (same genes) will both have bipolar I disorder (concordance) is around 40%, compared to about 5% in [[fraternal twins]].<ref name="Barnett2009" /><ref name="Kieseppa_2004">{{cite journal |vauthors=Kieseppä T, Partonen T, Haukka J, Kaprio J, Lönnqvist J | title = High Concordance of Bipolar I Disorder in a Nationwide Sample of Twins | journal = American Journal of Psychiatry | volume = 161 | issue = 10 | pages = 1814–1821 | year = 2004 | pmid = 15465978 | doi = 10.1176/appi.ajp.161.10.1814 }}</ref> A combination of bipolar I, II, and [[cyclothymia]] similarly produced rates of 42% and 11% (identical and fraternal twins, respectively).<ref name="Edvardsen2008" /> The rates of bipolar II combinations without bipolar I are lower{{Em dash}}bipolar II at 23 and 17%, and bipolar II combining with cyclothymia at 33 and 14%{{Em dash}}which may reflect relatively higher genetic [[Homogeneity and heterogeneity|heterogeneity]].<ref name="Edvardsen2008" />

The cause of bipolar disorders overlaps with major depressive disorder. When defining concordance as the co-twins having either bipolar disorder or major depression, then the concordance rate rises to 67% in identical twins and 19% in fraternal twins.<ref name=McGuffin2003>{{cite journal |vauthors=McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A | title = The Heritability of Bipolar Affective Disorder and the Genetic Relationship to Unipolar Depression | journal = Archives of General Psychiatry | volume = 60 | issue = 5 | pages = 497–502 | year = 2003 | pmid = 12742871 | doi = 10.1001/archpsyc.60.5.497 | doi-access = free }}</ref> The relatively low concordance between fraternal twins brought up together suggests that shared family environmental effects are limited, although the ability to detect them has been limited by small sample sizes.<ref name="Edvardsen2008" />

=== Genetic ===
[[Behavioral genetics|Behavioral genetic]] studies have suggested that many [[chromosomal]] regions and [[candidate gene]]s are related to bipolar disorder susceptibility with [[Polygenic disorder|each gene exerting a mild to moderate effect]].<ref name="Kerner2014">{{cite journal|author=Kerner B|date=February 2014|title=Genetics of bipolar disorder|journal=Appl Clin Genet|volume=7|pages=33–42|doi=10.2147/tacg.s39297|pmc=3966627|pmid=24683306 |doi-access=free }}</ref> The risk of bipolar disorder is nearly ten-fold higher in [[first-degree relatives]] of those with bipolar disorder than in the general population; similarly, the risk of major depressive disorder is three times higher in relatives of those with bipolar disorder than in the general population.<ref name="Barnett2009" />

Although the first [[genetic linkage]] finding for mania was in 1969,<ref>{{cite journal|author2-link=Paula Clayton|author3-link=George Winokur | vauthors = Reich T, Clayton PJ, Winokur G | s2cid = 33268 | title = Family history studies: V. The genetics of mania | journal = The American Journal of Psychiatry | volume = 125 | issue = 10 | pages = 1358–1369 | date = April 1969 | pmid = 5304735 | doi = 10.1176/ajp.125.10.1358 }}</ref> linkage studies have been inconsistent.<ref name="Barnett2009">{{cite journal | vauthors = Barnett JH, Smoller JW | title = The genetics of bipolar disorder | journal = Neuroscience | volume = 164 | issue = 1 | pages = 331–343 | date = November 2009 | pmid = 19358880 | pmc = 3637882 | doi = 10.1016/j.neuroscience.2009.03.080 }}</ref> Findings point strongly to heterogeneity, with different genes implicated in different families.<ref>{{cite journal |vauthors=Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger JI, Craddock N, DePaulo JR, Baron M, Gershon ES, Ekholm J, Cichon S, Turecki G, Claes S, Kelsoe JR, Schofield PR, Badenhop RF, Morissette J, Coon H, Blackwood D, McInnes LA, Foroud T, Edenberg HJ, Reich T, Rice JP, Goate A, McInnis MG, McMahon FJ, Badner JA, Goldin LR, Bennett P, Willour VL, Zandi PP, Liu J, Gilliam C, Juo SH, Berrettini WH, Yoshikawa T, Peltonen L, Lönnqvist J, Nöthen MM, Schumacher J, Windemuth C, Rietschel M, Propping P, Maier W, Alda M, Grof P, Rouleau GA, Del-Favero J, Van Broeckhoven C, Mendlewicz J, Adolfsson R, Spence MA, Luebbert H, Adams LJ, Donald JA, Mitchell PB, Barden N, Shink E, Byerley W, Muir W, Visscher PM, Macgregor S, Gurling H, Kalsi G, McQuillin A, Escamilla MA, Reus VI, Leon P, Freimer NB, Ewald H, Kruse TA, Mors O, Radhakrishna U, Blouin JL, Antonarakis SE, Akarsu N | title = Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part III: Bipolar Disorder | journal = The American Journal of Human Genetics | volume = 73 | issue = 1 | pages = 49–62 | year = 2003 | pmid = 12802785 | pmc = 1180589 | doi = 10.1086/376547 }}</ref> Robust and replicable genome-wide significant associations showed several common [[single-nucleotide polymorphism]]s (SNPs) are associated with bipolar disorder, including variants within the genes ''[[CACNA1C]]'', ''[[ODZ4]]'', and ''[[NCAN]]''.<ref name="Kerner2014" /><ref name="Craddock2013">{{cite journal |vauthors=Craddock N, Sklar P | title = Genetics of bipolar disorder | journal = Lancet | volume = 381 | issue = 9878 | pages = 1654–1662 | date = May 2013 | pmid = 23663951 | doi = 10.1016/S0140-6736(13)60855-7 | s2cid = 9502929 }}</ref> The largest and most recent [[genome-wide association study]] failed to find any locus that exerts a large effect, reinforcing the idea that no single gene is responsible for bipolar disorder in most cases.<ref name="Craddock2013" /> Polymorphisms in ''[[BDNF]]'', ''[[DRD4]]'', [[D-amino acid oxidase|''DAO'']], and ''[[TPH1]]'' have been frequently associated with bipolar disorder and were initially associated in a [[meta-analysis]], but this association disappeared after correction for [[multiple testing]].<ref>{{cite journal | vauthors = Seifuddin F, Mahon PB, Judy J, Pirooznia M, Jancic D, Taylor J, Goes FS, Potash JB, Zandi PP | title = Meta-analysis of genetic association studies on bipolar disorder | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 159B | issue = 5 | pages = 508–518 | date = July 2012 | pmid = 22573399 | pmc = 3582382 | doi = 10.1002/ajmg.b.32057 }}</ref> On the other hand, two polymorphisms in ''[[TPH2]]'' were identified as being associated with bipolar disorder.<ref>{{cite journal | vauthors = Gao J, Jia M, Qiao D, Qiu H, Sokolove J, Zhang J, Pan Z | title = TPH2 gene polymorphisms and bipolar disorder: A meta-analysis | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 171B | issue = 2 | pages = 145–152 | date = March 2016 | pmid = 26365518 | doi = 10.1002/ajmg.b.32381 | s2cid = 9467242 | doi-access = free }}</ref>

Due to the inconsistent findings in a [[genome-wide association study]], multiple studies have undertaken the approach of analyzing SNPs in biological pathways. Signaling pathways traditionally associated with bipolar disorder that have been supported by these studies include [[corticotropin-releasing hormone]] signaling, cardiac [[β-adrenergic]] signaling, [[phospholipase C]] signaling, [[glutamate]] receptor signaling,<ref>{{cite journal | vauthors = Torkamani A, Topol EJ, Schork NJ | title = Pathway analysis of seven common diseases assessed by genome-wide association | journal = Genomics | volume = 92 | issue = 5 | pages = 265–272 | date = November 2008 | pmid = 18722519 | pmc = 2602835 | doi = 10.1016/j.ygeno.2008.07.011 }}</ref> cardiac hypertrophy signaling, [[Wnt signaling pathway|Wnt signaling]], [[Notch signaling]],<ref>{{cite journal | vauthors = Pedroso I, Lourdusamy A, Rietschel M, Nöthen MM, Cichon S, McGuffin P, Al-Chalabi A, Barnes MR, Breen G | title = Common genetic variants and gene-expression changes associated with bipolar disorder are over-represented in brain signaling pathway genes | journal = Biological Psychiatry | volume = 72 | issue = 4 | pages = 311–317 | date = August 2012 | pmid = 22502986 | doi = 10.1016/j.biopsych.2011.12.031 | s2cid = 30065607 | url = https://zenodo.org/record/9822 }}</ref> and [[endothelin 1]] signaling. Of the 16 genes identified in these pathways, three were found to be dysregulated in the [[dorsolateral prefrontal cortex]] portion of the brain in post-mortem studies: ''[[CACNA1C]]'', ''[[GNG2]]'', and ''[[ITPR2]]''.<ref>{{cite journal | vauthors = Nurnberger JI, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I, Vawter MP, Kelsoe JR | title = Identification of pathways for bipolar disorder: a meta-analysis | journal = JAMA Psychiatry | volume = 71 | issue = 6 | pages = 657–664 | date = June 2014 | pmid = 24718920 | pmc = 4523227 | doi = 10.1001/jamapsychiatry.2014.176 }}</ref>

Bipolar disorder is associated with reduced expression of specific [[DNA repair]] enzymes and increased levels of oxidative [[DNA damage (naturally occurring)|DNA damages]].<ref name="pmid27126805">{{cite journal |vauthors=Raza MU, Tufan T, Wang Y, Hill C, Zhu MY |title=DNA Damage in Major Psychiatric Diseases |journal=Neurotox Res |volume=30 |issue=2 |pages=251–267 |date=August 2016 |pmid=27126805 |pmc=4947450 |doi=10.1007/s12640-016-9621-9 }}</ref> The AKAP11 gene was recently discovered as the first gene linked to bipolar disorder. The exomes of around 14,000 individuals with bipolar disorder were analysed and compared to those without the condition. The findings were combined with data from another study in the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA), examining the genome sequences of 24,000 people alongside the original 14,000 bipolar disorder cases. This study identified genetic variants, including the AKAP11 gene, associated with an increased risk of bipolar disorder. The AKAP11 gene's interaction with the GSK3B protein, a molecular target of lithium, points to a possible mechanism behind the medication's therapeutic effects.<ref>{{Cite web |first=Leah |last=Eisenstadt |date=2022-04-06 |title=Researchers find first strong genetic risk factor for bipolar disorder |url=https://www.broadinstitute.org/news/researchers-find-first-strong-genetic-risk-factor-bipolar-disorder |access-date=2025-03-06 |website=Broad Institute |language=en}}</ref>

=== Environmental ===
[[Psychosocial]] factors play a significant role in the development and course of bipolar disorder, and individual psychosocial variables may interact with genetic dispositions.<ref name="Serretti">{{cite journal |vauthors=Serretti A, Mandelli L | title = The genetics of bipolar disorder: Genome 'hot regions,' genes, new potential candidates and future directions | journal = Molecular Psychiatry | volume = 13 | issue = 8 | pages = 742–71 | year = 2008 | pmid = 18332878 | doi = 10.1038/mp.2008.29 | doi-access = free }}</ref><ref>{{Cite journal |last1=Robinson |first1=Natassia |last2=Bergen |first2=Sarah E. |date=2021-06-28 |title=Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions |journal=Frontiers in Genetics |volume=12 |doi=10.3389/fgene.2021.686666 |doi-access=free |pmid=34262598 |issn=1664-8021|pmc=8273311 }}</ref> Recent life events and interpersonal relationships likely contribute to the onset  and recurrence of bipolar mood episodes, just as they do for unipolar depression.<ref name="Geddestreatment" /> In surveys, 30–50% of adults diagnosed with bipolar disorder report traumatic/abusive experiences in childhood, which is associated with earlier onset, a higher rate of suicide attempts, and more co-occurring disorders such as [[PTSD|post-traumatic stress disorder]].<ref name="Brietzke2012">{{cite journal | vauthors = Brietzke E, Kauer Sant'anna M, Jackowski A, Grassi-Oliveira R, Bucker J, Zugman A, Mansur RB, Bressan RA | title = Impact of childhood stress on psychopathology | journal = Rev Bras Psiquiatr | volume = 34 | issue = 4 | pages = 480–488 | date = December 2012 | pmid = 23429820 | doi = 10.1016/j.rbp.2012.04.009 | doi-access = free }}</ref> Subtypes of abuse, such as sexual and emotional abuse, also contribute to violent behaviors seen in patients with bipolar disorder.<ref>{{cite journal | vauthors = Bal NB, Özalp E, Teksin MG, Kotan Z, Karslıoğlu EH, Çayköylü A | title = Childhood Trauma as an Environmental Determinant of Risk of Violence in Bipolar Disorder | journal = Noro Psikiyatri Arsivi | volume = 60 | issue = 4 | pages = 344–349 | year = 2023 | pmid = 38077849 | pmc = 10709710 | doi = 10.29399/npa.28340 }}</ref> The number of reported stressful events in childhood is higher in those with an adult diagnosis of bipolar spectrum disorder than in those without, particularly events stemming from a harsh environment rather than from the child's own behavior.<ref>{{cite journal |vauthors=Miklowitz DJ, Chang KD | title = Prevention of bipolar disorder in at-risk children: Theoretical assumptions and empirical foundations | journal = Development and Psychopathology | volume = 20 | issue = 3 | pages = 881–497 | year = 2008 | pmid = 18606036 | pmc = 2504732 | doi = 10.1017/S0954579408000424 }}</ref> Acutely, mania can be induced by [[sleep deprivation]] in around 30% of people with bipolar disorder.<ref>{{cite journal | vauthors = Young JW, Dulcis D | title = Investigating the mechanism(s) underlying switching between states in bipolar disorder | journal = [[European Journal of Pharmacology]] | volume = 759 | pages = 151–162 | date = July 2015 | pmid = 25814263 | pmc = 4437855 | doi = 10.1016/j.ejphar.2015.03.019 }}</ref>

=== Neurological ===
Less commonly, bipolar disorder or a bipolar-like disorder may occur as a result of or in association with a neurological condition or injury including stroke, [[traumatic brain injury]], [[HIV/AIDS|HIV infection]], [[multiple sclerosis]], [[porphyria]], and rarely [[temporal lobe epilepsy]].<ref>Murray ED, Buttner N, Price BH. (2012) "Depression and Psychosis in Neurological Practice". In: ''Neurology in Clinical Practice'', 6th Edition. Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.) Butterworth Heinemann. {{ISBN|978-1-4377-0434-1}}</ref>