title: Shared Predisposition in the Association Between Cannabis Use and Subcortical Brain Structure.
abstract: OBJECTIVE
  Prior neuroimaging studies have suggested that alterations in brain structure may be a consequence of cannabis use. Siblings discordant for cannabis use offer an opportunity to use cross-sectional data to disentangle such causal hypotheses from shared effects of genetics and familial environment on brain structure and cannabis use.
  
  
  OBJECTIVE
  To determine whether cannabis use is associated with differences in brain structure in a large sample of twins/siblings and to examine sibling pairs discordant for cannabis use to separate potential causal and predispositional factors linking lifetime cannabis exposure to volumetric alterations.
  
  
  METHODS
  Cross-sectional diagnostic interview, behavioral, and neuroimaging data were collected from community sampling and established family registries from August 2012 to September 2014. This study included data from 483 participants (22-35 years old) enrolled in the ongoing Human Connectome Project, with 262 participants reporting cannabis exposure (ie, ever used cannabis in their lifetime).
  
  
  METHODS
  Cannabis exposure was measured with the Semi-Structured Assessment for the Genetics of Alcoholism. Whole-brain, hippocampus, amygdala, ventral striatum, and orbitofrontal cortex volumes were related to lifetime cannabis use (ever used, age at onset, and frequency of use) using linear regressions. Genetic (ρg) and environmental (ρe) correlations between cannabis use and brain volumes were estimated. Linear mixed models were used to examine volume differences in sex-matched concordant unexposed (n = 71 pairs), exposed (n = 81 pairs), or exposure discordant (n = 89 pairs) sibling pairs.
  
  
  RESULTS
  Among 483 study participants, cannabis exposure was related to smaller left amygdala (approximately 2.3%; P = .007) and right ventral striatum (approximately 3.5%; P < .005) volumes. These volumetric differences were within the range of normal variation. The association between left amygdala volume and cannabis use was largely owing to shared genetic factors (ρg = -0.43; P = .004), while the origin of the association with right ventral striatum volumes was unclear. Importantly, brain volumes did not differ between sex-matched siblings discordant for use (fixed effect = -7.43; t = -0.93, P = .35). Both the exposed and unexposed siblings in pairs discordant for cannabis exposure showed reduced amygdala volumes relative to members of concordant unexposed pairs (fixed effect = 12.56; t = 2.97; P = .003).
  
  
  CONCLUSIONS
  In this study, differences in amygdala volume in cannabis users were attributable to common predispositional factors, genetic or environmental in origin, with little support for causal influences. Causal influences, in isolation or in conjunction with predispositional factors, may exist for other brain regions (eg, ventral striatum) or at more severe levels of cannabis involvement and deserve further study.
authors: The Program in Neuroscience, Washington University in St Louis, St Louis, Missouri.
authors: David
authors: D
authors: Pagliaccio
authors: Department of Psychiatry, Washington University in St Louis, St Louis, Missouri3Department of Psychology, Washington University in St Louis, St Louis, Missouri4Department of Radiology, Washington University in St Louis, St Louis, Missouri.
authors: Deanna M
authors: DM
authors: Barch
authors: Department of Psychology, Washington University in St Louis, St Louis, Missouri.
authors: Ryan
authors: R
authors: Bogdan
authors: Department of PsychologicalSciences, University of Missouri, Columbia.
authors: Phillip K
authors: PK
authors: Wood
authors: Institute of Psychiatry, Psychology and Neuroscience, Department of Addictions, King's College London, London, England.
authors: Michael T
authors: MT
authors: Lynskey
authors: Department of Psychiatry, Washington University in St Louis, St Louis, Missouri.
authors: Andrew C
authors: AC
authors: Heath
authors: Department of Psychiatry, Washington University in St Louis, St Louis, Missouri.
authors: Arpana
authors: A
authors: Agrawal
mesh_terms: D000328:Adult; D000679:Amygdala / Q000473:pathology; D001921:Brain / Q000473:pathology*; D003430:Cross-Sectional Studies; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008385:Marijuana Smoking / Q000235:genetics / Q000473:pathology*; D009929:Organ Size; D035781:Siblings; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*; D066328:Ventral Striatum / Q000473:pathology