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The biological effects of single genetic variants might differ depending on epistatic interactions that can be functionally multi\u2010directional and non\u2010linear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We performed behavioural and neurochemical assessments in genetically modified mice and behavioural assessments and genetic screening in human patients with 22q11.2 deletion syndrome (22q11.2DS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Here, we confirm a genetic interaction between the <jats:italic>Comt<\/jats:italic> (catechol\u2010O\u2010methyltransferase, human orthologue: <jats:italic>COMT<\/jats:italic>) and <jats:italic>Dtnbp1<\/jats:italic> (dystrobrevin binding protein 1, alias dysbindin, human orthologue: <jats:italic>DTNBP1<\/jats:italic>) genes that modulate cortical and striatal dopaminergic signalling in a manner not predictable by the effects of each single gene. In mice, <jats:italic>Comt<\/jats:italic>\u2010by\u2010<jats:italic>Dtnbp1<\/jats:italic> concomitant reduction leads to a hypoactive mesocortical and a hyperactive mesostriatal dopamine pathway, associated with specific cognitive abnormalities. Like mice, in subjects with the 22q11.2DS (characterized by <jats:italic>COMT<\/jats:italic> hemideletion and dopamine alterations), <jats:italic>COMT<\/jats:italic>\u2010by\u2010<jats:italic>DTNBP1<\/jats:italic> concomitant reduction was associated with analogous cognitive disturbances. We then developed an easy and inexpensive colourimetric kit for the genetic screening of common <jats:italic>COMT<\/jats:italic> and <jats:italic>DTNBP1<\/jats:italic> functional genetic variants for clinical application.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These findings illustrate an epistatic interaction of two dopamine\u2010related genes and their functional effects, supporting the need to address genetic interaction mechanisms at the base of complex behavioural traits.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16147","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T10:47:19Z","timestamp":1684838839000},"page":"2514-2531","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dopaminergic signalling and behavioural alterations by <i>Comt<\/i>\u2013<i>Dtnbp1<\/i> genetic interaction and their clinical 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