Editing Bipolar disorder (section)

=== 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>