Editing Schizophrenia (section)

===Genetic===
Estimates of the [[heritability]] of schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk of schizophrenia are associated with genetics.<ref name=vandeLeemput2016/><ref name=Her2011/> These estimates vary because of the [[behavioural genetics|difficulty in separating]] genetic and environmental influences, and their accuracy has been queried.<ref>{{cite journal | vauthors = O'Donovan MC, Williams NM, Owen MJ | title = Recent advances in the genetics of schizophrenia | journal = Human Molecular Genetics | volume = 12 Spec No 2 | pages = R125–133 | date = October 2003 | pmid = 12952866 | doi = 10.1093/hmg/ddg302 | doi-access = free }}</ref><ref name=Torrey2019>{{Cite journal |vauthors=Torrey EF, Yolken RH |s2cid=173991937 |date=August 2019 |title=Schizophrenia as a pseudogenetic disease: A call for more gene-environmental studies |journal=Psychiatry Research |volume=278 |pages=146–150 |doi=10.1016/j.psychres.2019.06.006|pmid=31200193 }}</ref> The greatest risk factor for developing schizophrenia is having a [[first-degree relative]] with the disease (risk is 6.5%); more than 40% of [[Twin#Monozygotic (identical) twins|identical twins]] of those with schizophrenia are also affected.<ref name=BMJ07>{{cite journal | vauthors = Picchioni MM, Murray RM | title = Schizophrenia | journal = BMJ | volume = 335 | issue = 7610 | pages = 91–95 | date = July 2007 | pmid = 17626963 | pmc = 1914490 | doi = 10.1136/bmj.39227.616447.BE }}</ref> If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%.<ref name=Her2011>{{cite book|title=Adult psychopathology and diagnosis |year=2011 |publisher=John Wiley & Sons |isbn=978-1-118-13884-7 |chapter-url= https://books.google.com/books?id=iJtzm1KfU5oC&pg=PT282 |chapter= Chapter 8: Schizophrenia: Etiological considerations| veditors = Hersen M, Beidel DC |edition=6th| vauthors = Combs DR, Mueser KT, Gutierrez MM }}</ref> However, the ''DSM-5'' indicates that most people with schizophrenia have no family history of psychosis.<ref name=DSM5/> Results of [[candidate gene]] studies of schizophrenia have generally failed to find consistent associations,<ref>{{cite journal | vauthors = Farrell MS, Werge T, Sklar P, Owen MJ, Ophoff RA, O'Donovan MC, Corvin A, Cichon S, Sullivan PF | title = Evaluating historical candidate genes for schizophrenia | journal = Molecular Psychiatry | volume = 20 | issue = 5 | pages = 555–562 | date = May 2015 | pmid = 25754081 | pmc = 4414705 | doi = 10.1038/mp.2015.16 }}</ref> and the [[genetic loci]] identified by [[genome-wide association studies]] explain only a small fraction of the variation in the disease.<ref>{{Cite book |url= https://books.google.com/books?id=7ukmDAAAQBAJ |title=Schizophrenia and Psychotic Spectrum Disorders | vauthors = Schulz SC, Green MF, Nelson KJ |date=2016 |publisher=Oxford University Press |isbn=9780199378067 |pages=124–125 }}</ref>

Many [[genes]] are known to be involved in schizophrenia, each with small effects and unknown [[Gene#Molecular inheritance|transmission]] and [[Gene expression|expression]].<ref name=vandeLeemput2016/><ref>{{cite journal | vauthors = Schork AJ, Wang Y, Thompson WK, Dale AM, Andreassen OA | title = New statistical approaches exploit the polygenic architecture of schizophrenia—implications for the underlying neurobiology | journal = Current Opinion in Neurobiology | volume = 36 | pages = 89–98 | date = February 2016 | pmid = 26555806 | pmc = 5380793 | doi = 10.1016/j.conb.2015.10.008 }}</ref><ref>{{cite journal|vauthors= Coelewij L, Curtis D|title=Mini-review: Update on the genetics of schizophrenia|journal=Annals of Human Genetics|volume=82|issue=5|year= 2018|pages=239–243|issn=0003-4800|doi=10.1111/ahg.12259|pmid= 29923609|s2cid=49311660|url=https://discovery.ucl.ac.uk/id/eprint/10064654/ |doi-access=free}}</ref> The summation of these effect sizes into a [[polygenic score|polygenic risk score]] can explain at least 7% of the variability in liability for schizophrenia.<ref>{{cite journal | vauthors = Kendler KS | title = The Schizophrenia Polygenic Risk Score: To What Does It Predispose in Adolescence? | journal = JAMA Psychiatry | volume = 73 | issue = 3 | pages = 193–194 | date = March 2016 | pmid = 26817666 | doi = 10.1001/jamapsychiatry.2015.2964 }}</ref> Around 5% of cases of schizophrenia are understood to be at least partially attributable to rare [[copy number variation]]s (CNVs); these [[structural variation]]s are associated with known genomic disorders involving [[Deletion (genetics)|deletions]] at [[chromosome 22#Chromosomal conditions|22q11.2]] ([[DiGeorge syndrome]]) and [[Chromosome 17#Diseases and disorders|17q12]] ([[17q12 microdeletion syndrome]]), duplications at [[chromosome 16#Cytogenetic band|16p11.2]] (most frequently found) and deletions at [[chromosome 15#Cytogenetic band|15q11.2]] ([[Burnside–Butler syndrome]]).<ref name=Lowther2017p82>{{cite journal | vauthors = Lowther C, Costain G, Baribeau DA, Bassett AS | s2cid = 4776174 | title = Genomic Disorders in Psychiatry—What Does the Clinician Need to Know? | journal = Current Psychiatry Reports | volume = 19 | issue = 11 | page = 82 | date = September 2017 | doi = 10.1007/s11920-017-0831-5 | pmid = 28929285 }}</ref> Some of these CNVs increase the risk of developing schizophrenia by as much as 20-fold, and are frequently comorbid with autism and intellectual disabilities.<ref name=Lowther2017p82/>

The genes [[CRHR1]] and [[CRHBP]] are associated with the severity of suicidal behavior. These genes code for stress response proteins needed in the control of the [[HPA axis]], and their interaction can affect this axis. Response to stress can cause lasting changes in the [[HPA axis#Stress and development|function of the HPA axis]] possibly disrupting the negative feedback mechanism, [[homeostasis]], and the regulation of emotion leading to altered behaviors.<ref name=Perkovic2017/>

The question of how schizophrenia could be primarily genetically influenced, given that people with schizophrenia have lower fertility rates, is a paradox. It is expected that [[allele|genetic variants]] that increase the risk of schizophrenia would be selected against, due to their negative effects on [[reproductive fitness]]. A number of potential explanations have been proposed, including that [[allele]]s associated with schizophrenia risk confers a fitness advantage in unaffected individuals.<ref>{{Cite journal |vauthors= Bundy H, Stahl D, MacCabe JH |date=February 2011 |title=A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives: Fertility in schizophrenia |journal=Acta Psychiatrica Scandinavica |volume=123 |issue=2 |pages=98–106 |doi= 10.1111/j.1600-0447.2010.01623.x|pmid=20958271 |s2cid=45179016 }}</ref><ref>{{Cite journal |vauthors= van Dongen J, Boomsma DI |date=March 2013 |title=The evolutionary paradox and the missing heritability of schizophrenia |journal=American Journal of Medical Genetics Part B: Neuropsychiatric Genetics |volume=162 |issue=2 |pages=122–136 |doi= 10.1002/ajmg.b.32135|pmid=23355297 |s2cid=9648115 }}</ref> While some evidence has not supported this idea,<ref name=Torrey2019/> others propose that a large number of alleles each contributing a small amount can persist.<ref>{{cite journal |vauthors= Owen MJ, Sawa A, Mortensen PB |title=Schizophrenia |journal=Lancet |date=2 July 2016 |volume=388 |issue=10039 |pages=86–97 |doi=10.1016/S0140-6736(15)01121-6 |pmid= 26777917|pmc=4940219}}</ref>

A meta-analysis found that oxidative [[DNA damage (naturally occurring)|DNA damage]] was significantly increased in schizophrenia.<ref name = Goh2021>{{cite journal |vauthors=Goh XX, Tang PY, Tee SF |title= 8-Hydroxy-2'-Deoxyguanosine and Reactive Oxygen Species as Biomarkers of Oxidative Stress in Mental Illnesses: A Meta-Analysis |journal= Psychiatry Investig |volume=18 |issue=7 |pages=603–618 |date=July 2021 |pmid=34340273 |pmc=8328836 |doi=10.30773/pi.2020.0417 |type= Meta-analysis}}</ref>