Editing Attention deficit hyperactivity disorder (section)

=== Genetics ===
{{See also|Missing heritability problem}}

In November 1999, ''[[Biological Psychiatry (journal)|Biological Psychiatry]]'' published a [[literature review]] by psychiatrists [[Joseph Biederman]] and Thomas Spencer found the average [[heritability]] estimate of ADHD from [[Twin study|twin studies]] to be 0.8,<ref>{{cite journal |vauthors=Biederman J, Spencer T |title=Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder |journal=[[Biological Psychiatry (journal)|Biological Psychiatry]] |volume=46 |issue=9 |pages=1234–1242 |date=November 1999 |pmid=10560028 |doi=10.1016/S0006-3223(99)00192-4 |publisher=[[Elsevier]] |s2cid=45497168 |author1-link=Joseph Biederman}}</ref> while a subsequent [[Family study|family]], twin, and [[Adoption study|adoption studies]] literature review published in ''[[Molecular Psychiatry]]'' in April 2019 by psychologists [[Stephen Faraone]] and Henrik Larsson that found an average heritability estimate of 0.74.<ref name="Faraone_2019" /> Additionally, [[Evolutionary psychiatry|evolutionary psychiatrist]] [[Randolph M. Nesse]] has argued that the 5:1 [[Sex differences in psychology|male-to-female sex ratio]] in the [[Mental disorders and gender|epidemiology of ADHD]] suggests that ADHD may be the [[Variability hypothesis|end of a continuum where males are overrepresented at the tails]], citing clinical psychologist [[Simon Baron-Cohen]]'s [[Empathising–systemising theory|suggestion]] for the [[Sex differences in autism|sex ratio in the epidemiology of autism]] as an analogue.<ref name="Baron-Cohen 2002">{{cite journal |vauthors=Baron-Cohen S |title=The extreme male brain theory of autism |journal=[[Trends in Cognitive Sciences]] |volume=6 |issue=6 |pages=248–254 |date=June 2002 |pmid=12039606 |doi=10.1016/S1364-6613(02)01904-6 |url=https://www.cell.com/trends/cognitive-sciences/fulltext/S1364-6613(02)01904-6 |access-date=9 July 2020 |publisher=[[Elsevier]] |url-status=live |s2cid=8098723 |archive-url=https://web.archive.org/web/20130703172532/http://www.cell.com/trends/cognitive-sciences/fulltext/S1364-6613(02)01904-6 |archive-date=3 July 2013 |author-link=Simon Baron-Cohen}}</ref><ref name="Nesse 2005 p. 918">{{cite book |vauthors=Nesse RM |author1-link=Randolph M. Nesse |veditors=Buss DM |editor-link=David Buss |title=The Handbook of Evolutionary Psychology |chapter=32. Evolutionary Psychology and Mental Health |page=918 |year=2005 |edition=1st |place=[[Hoboken, New Jersey|Hoboken, NJ]] |publisher=[[Wiley (publisher)|Wiley]] |isbn=978-0-471-26403-3}}</ref><ref name="Nesse 2016 p. 1019">{{cite book |vauthors=Nesse RM |author-link1=Randolph M. Nesse |veditors=Buss DM |editor1-link=David Buss |year=2016 |orig-date=2005 |title=The Handbook of Evolutionary Psychology, Volume 2: Integrations |edition=2nd |chapter=43. Evolutionary Psychology and Mental Health |page=1019 |place=[[Hoboken, New Jersey|Hoboken, NJ]] |publisher=[[Wiley (publisher)|Wiley]] |isbn=978-1-118-75580-8}}</ref>

[[Evolution by natural selection|Natural selection]] has been acting against the genetic variants for ADHD over the course of at least 45,000 years, indicating that it was not an adaptive trait in ancient times.<ref>{{cite journal |vauthors=Esteller-Cucala P, Maceda I, Børglum AD, Demontis D, Faraone SV, Cormand B, Lao O |title=Genomic analysis of the natural history of attention-deficit/hyperactivity disorder using Neanderthal and ancient Homo sapiens samples |journal=[[Scientific Reports]] |volume=10 |issue=1 |page=8622 |date=May 2020 |pmid=32451437 |pmc=7248073 |doi=10.1038/s41598-020-65322-4 |bibcode=2020NatSR..10.8622E}}</ref> The disorder may remain at a stable rate by the balance of genetic mutations and removal rate (natural selection) across generations; over thousands of years, these genetic variants become more stable, decreasing disorder prevalence.<ref>{{cite journal |vauthors=Keller MC |title=The evolutionary persistence of genes that increase mental disorders risk. |journal=[[Current Directions in Psychological Science]] |date=December 2008 |volume=17 |issue=6 |pages=395–399 |doi=10.1111/j.1467-8721.2008.00613|doi-broken-date=24 April 2025 }}</ref> Throughout human evolution, the executive functions involved in ADHD likely provide the capacity to bind contingencies across time thereby directing behaviour toward future over immediate events so as to maximise future social consequences for humans.<ref>{{cite book |vauthors=Barkley RA |date=2004 |chapter=Attention-deficit/hyperactivity disorder and self-regulation: Taking an evolutionary perspective on executive functioning. |veditors=Baumeister RF, Vohs KD |title=Handbook of self-regulation: Research, theory, and applications |pages=301–323 |publisher=[[Guilford Press]] |url=https://psycnet.apa.org/record/2004-00163-014}}</ref>

ADHD has a high [[heritability]] of 74%, meaning that 74% of the presence of ADHD in the population is due to genetic factors. There are multiple gene variants which each slightly increase the likelihood of a person having ADHD; it is [[polygenic disease|polygenic]] and thus arises through the accumulation of many genetic risks each having a very small effect.<ref name="Faraone_2021" /><ref name="Faraone_2019" /> The siblings of children with ADHD are three to four times more likely to develop the disorder than siblings of children without the disorder.<ref>{{cite book |vauthors=Nolen-Hoeksema S |title=Abnormal Psychology |year=2013 |isbn=978-0-07-803538-8 |page=267 |publisher=[[McGraw-Hill Education]] |edition=6th}}</ref>

The association of maternal smoking observed in large population studies disappears after adjusting for family history of ADHD, which indicates that the association between maternal smoking during pregnancy and ADHD is due to familial or genetic factors that increase the risk for the confluence of smoking and ADHD.<ref>{{cite journal |vauthors=Skoglund C, Chen Q, D'Onofrio BM, Lichtenstein P, Larsson H |title=Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring |journal=[[Journal of Child Psychology and Psychiatry|Journal of Child Psychology and Psychiatry, and Allied Disciplines]] |volume=55 |issue=1 |pages=61–68 |date=January 2014 |pmid=25359172 |pmc=4217138 |doi=10.1111/jcpp.12124}}</ref><ref>{{cite journal |vauthors=Obel C, Zhu JL, Olsen J, Breining S, Li J, Grønborg TK, Gissler M, Rutter M |title=The risk of attention deficit hyperactivity disorder in children exposed to maternal smoking during pregnancy - a re-examination using a sibling design |journal=[[Journal of Child Psychology and Psychiatry|Journal of Child Psychology and Psychiatry, and Allied Disciplines]] |volume=57 |issue=4 |pages=532–537 |date=April 2016 |pmid=26511313 |doi=10.1111/jcpp.12478 |url=https://kclpure.kcl.ac.uk/portal/en/publications/b67579b4-68c2-4010-86c4-0392822d2662}}</ref>

ADHD presents with reduced size, functional connectivity and activation<ref name="Faraone_2021" /> as well as low noradrenergic and dopaminergic functioning<ref name="Biederman_2005" /><ref>{{cite journal |vauthors=Hinshaw SP |title=Attention Deficit Hyperactivity Disorder (ADHD): Controversy, Developmental Mechanisms, and Multiple Levels of Analysis |journal=[[Annual Review of Clinical Psychology]] |volume=14 |issue=1 |pages=291–316 |date=May 2018 |pmid=29220204 |doi=10.1146/annurev-clinpsy-050817-084917 }}</ref> in brain regions and networks crucial for executive functioning and self-regulation.<ref name="Faraone_2021" /><ref name="Barkley_2011a" /><ref name="Antshel_2014" /> Typically, a number of genes are involved, many of which directly affect brain functioning and neurotransmission.<ref name="Faraone_2021" /> Those involved with dopamine include [[Dopamine transporter|DAT]], [[DRD4]], [[DRD5]], [[TAAR1]], [[MAOA]], [[Catechol O-methyltransferase|COMT]], and [[Dopamine-beta-hydroxylase|DBH.]]<ref name="Kebir_2011">{{cite journal |vauthors=Kebir O, Joober R |title=Neuropsychological endophenotypes in attention-deficit/hyperactivity disorder: a review of genetic association studies |journal=[[European Archives of Psychiatry and Clinical Neuroscience]] |volume=261 |issue=8 |pages=583–594 |date=December 2011 |pmid=21409419 |doi=10.1007/s00406-011-0207-5 |s2cid=21383749}}</ref><ref name="Berry_2007" /><ref>{{cite journal |vauthors=Sotnikova TD, Caron MG, Gainetdinov RR |title=Trace amine-associated receptors as emerging therapeutic targets |journal=[[Molecular Pharmacology]] |volume=76 |issue=2 |pages=229–235 |date=August 2009 |pmid=19389919 |pmc=2713119 |doi=10.1124/mol.109.055970}}</ref> Other genes associated with ADHD include [[Serotonin transporter|SERT]], [[HTR1B]], [[SNAP25]], [[GRIN2A]], [[ADRA2A]], [[TPH2]], and [[Brain-derived neurotrophic factor|BDNF]].<ref name="Gizer_2009">{{cite journal |vauthors=Gizer IR, Ficks C, Waldman ID |title=Candidate gene studies of ADHD: a meta-analytic review |journal=[[Human Genetics]] |volume=126 |issue=1 |pages=51–90 |date=July 2009 |pmid=19506906 |doi=10.1007/s00439-009-0694-x |s2cid=166017}}</ref> A common variant of a gene called [[latrophilin 3]] is estimated to be responsible for about 9% of cases and when this variant is present, people are particularly responsive to stimulant medication.<ref>{{cite journal |vauthors=Arcos-Burgos M, Muenke M |title=Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD |journal=Attention Deficit and Hyperactivity Disorders |volume=2 |issue=3 |pages=139–147 |date=November 2010 |pmid=21432600 |pmc=3280610 |doi=10.1007/s12402-010-0030-2}}</ref> The [[DRD4–7R|7 repeat variant of dopamine receptor D4]] (DRD4–7R) causes increased inhibitory effects induced by [[dopamine]] and is associated with ADHD. The DRD4 receptor is a [[G protein-coupled receptor]] that inhibits [[adenylyl cyclase]]. The DRD4–7R mutation results in a wide range of behavioural [[phenotype]]s, including ADHD symptoms reflecting split attention.<ref>{{cite journal |vauthors=Nikolaidis A, Gray JR |title=ADHD and the DRD4 exon III 7-repeat polymorphism: an international meta-analysis |journal=[[Social Cognitive and Affective Neuroscience]] |volume=5 |issue=2–3 |pages=188–193 |date=June 2010 |pmid=20019071 |pmc=2894686 |doi=10.1093/scan/nsp049}}</ref> The DRD4 gene is both linked to novelty seeking and ADHD. The genes [[glucose-fructose oxidoreductase|GFOD1]] and [[T-cadherin|CDH13]] show strong genetic associations with ADHD. CDH13's association with ASD, [[schizophrenia]], bipolar disorder, and [[Depression (mood)|depression]] make it an interesting candidate causative gene.<ref name="Grimm_2020" /> Another candidate causative gene that has been identified is [[Latrophilin 3|ADGRL3]]. In [[zebrafish]], knockout of this gene causes a loss of dopaminergic function in the ventral [[diencephalon]] and the fish display a hyperactive/impulsive [[phenotype]].<ref name="Grimm_2020" />

For [[genetic variation]] to be used as a tool for diagnosis, more validating studies need to be performed. However, smaller studies have shown that [[genetic polymorphism]]s in genes related to [[catecholaminergic]] neurotransmission or the [[SNARE (protein)|SNARE]] complex of the [[synapse]] can reliably predict a person's response to [[Stimulant|stimulant medication]].<ref name="Grimm_2020" /> Rare genetic variants show more relevant clinical significance as their penetrance (the chance of developing the disorder) tends to be much higher.<ref name="Zayats_2020">{{cite journal |vauthors=Zayats T, Neale BM |title=Recent advances in understanding of attention deficit hyperactivity disorder (ADHD): how genetics are shaping our conceptualization of this disorder |journal=F1000Research |volume=8 |page=2060 |date=12 February 2020 |pmid=31824658 |pmc=6896240 |doi=10.12688/f1000research.18959.2 |doi-access=free}}</ref> However their usefulness as tools for diagnosis is limited as no single gene predicts ADHD. ASD shows genetic overlap with ADHD at both common and rare levels of genetic variation.<ref name="Zayats_2020" />