biostudies-literatureHarper JNational Institute on Alcohol Abuse and AlcoholismNIBIB NIH HHSNIDA NIH HHSCollege of Liberal Arts, University of MinnesotaNIAAA NIH HHSNational Institute on Drug AbuseNIH HHS2548-2558https://www.ebi.ac.uk/biostudies/studies/S-EPMC8328872biostudies-literatureUnknown116(9)<h4>Background/aims</h4>Research linking orbitofrontal cortex (OFC) structure and substance use disorders (SUDs) is largely correlational and often implies a causal effect of addiction/substance exposure on the brain, but familial risk factors (e.g. genetic liability) may confound these associations. We tested whether associations between alcohol, cannabis and tobacco use disorders and OFC thickness reflected the potential causal effects of familial risk or SUDs-related consequences (e.g. substance exposure).<h4>Design</h4>A co-twin control/discordant twin design separated familial risk confounding from SUD-related consequences.<h4>Setting/participants</h4>A population-based sample of 436 24-year-old twins (62% monozygotic) from the Minnesota Twin Family Study, USA.<h4>Measurements</h4>Alcohol, cannabis and tobacco use disorders were assessed using the Composite International Diagnostic Interview-Substance Abuse Module. Cortical thickness of the medial and lateral OFC (mOFC and lOFC, respectively) was assessed using magnetic resonance imaging (MRI).<h4>Findings</h4>Lower mOFC (P-values ≤ 0.006) but not lOFC (P-values ≥ 0.190) thickness was observed in diagnosed individuals (n = 185) relative to non-SUD controls (n = 251). Co-twin control analyses offered evidence that mOFC associations were consistent with familial risk across SUDs (between-pair effect: P-values ≤ 0.047) and the independent consequences of having an alcohol or cannabis use disorder (within-pair effect: P-values ≤ 0.024). That is, within alcohol/cannabis discordant twin pairs, affected twins had significantly lower mOFC thickness compared with their unaffected co-twins.<h4>Conclusions</h4>A confounder-adjusted analysis of the Minnesota Twin Family Study appeared to indicate that, beyond a substance use disorders general familial risk effect, the experience of an alcohol or cannabis use disorder in emerging adulthood reduces the thickness of the medial orbitofrontal cortex, a region associated with value-guided decision-making.Addiction (Abingdon, England)Orbitofrontal cortex thickness and substance use disorders in emerging adulthood: causal inferences from a co-twin control/discordant twin study.PMC8328872R01DA036216R21 AA026632R01 DA036216R21AA026632P41 EB027061T32 DA037183T32DA037183K01 DA037280S10 OD017974R21AA026919K01DA037280R21 AA026919Thomas KMMalone SMIacono WGWilson SHunt RHHarper JfalseOrbitofrontal cortex thickness and substance use disorders in emerging adulthood: causal inferences from a co-twin control/discordant twin study.<h4>Background/aims</h4>Research linking orbitofrontal cortex (OFC) structure and substance use disorders (SUDs) is largely correlational and often implies a causal effect of addiction/substance exposure on the brain, but familial risk factors (e.g. genetic liability) may confound these associations. We tested whether associations between alcohol, cannabis and tobacco use disorders and OFC thickness reflected the potential causal effects of familial risk or SUDs-related consequences (e.g. substance exposure).<h4>Design</h4>A co-twin control/discordant twin design separated familial risk confounding from SUD-related consequences.<h4>Setting/participants</h4>A population-based sample of 436 24-year-old twins (62% monozygotic) from the Minnesota Twin Family Study, USA.<h4>Measurements</h4>Alcohol, cannabis and tobacco use disorders were assessed using the Composite International Diagnostic Interview-Substance Abuse Module. Cortical thickness of the medial and lateral OFC (mOFC and lOFC, respectively) was assessed using magnetic resonance imaging (MRI).<h4>Findings</h4>Lower mOFC (P-values ≤ 0.006) but not lOFC (P-values ≥ 0.190) thickness was observed in diagnosed individuals (n = 185) relative to non-SUD controls (n = 251). Co-twin control analyses offered evidence that mOFC associations were consistent with familial risk across SUDs (between-pair effect: P-values ≤ 0.047) and the independent consequences of having an alcohol or cannabis use disorder (within-pair effect: P-values ≤ 0.024). That is, within alcohol/cannabis discordant twin pairs, affected twins had significantly lower mOFC thickness compared with their unaffected co-twins.<h4>Conclusions</h4>A confounder-adjusted analysis of the Minnesota Twin Family Study appeared to indicate that, beyond a substance use disorders general familial risk effect, the experience of an alcohol or cannabis use disorder in emerging adulthood reduces the thickness of the medial orbitofrontal cortex, a region associated with value-guided decision-making.2021-01-01T00:00:00Z2021 Sep2025-04-18T15:25:02.696Z2025-04-07T02:03:01.498ZS-EPMC83288723362076310.1111/add.15447