Dataset Information

Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence.

ABSTRACT: IMPORTANCE:Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure. OBJECTIVE:To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS:Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014. MAIN OUTCOMES AND MEASURES:Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score. RESULTS:Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P?=?.009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137?=?-2.36; P?=?.02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (?61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01-0.12]; P?=?.02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 [95% CI, 0.03-0.18]; P?=?.004). CONCLUSIONS AND RELEVANCE:Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.

SUBMITTER: French L

PROVIDER: S-EPMC5075969 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence.

French Leon L Gray Courtney C Leonard Gabriel G Perron Michel M Pike G Bruce GB Richer Louis L Séguin Jean R JR Veillette Suzanne S Evans C John CJ Artiges Eric E Banaschewski Tobias T Bokde Arun W L AW Bromberg Uli U Bruehl Ruediger R Buchel Christian C Cattrell Anna A Conrod Patricia J PJ Flor Herta H Frouin Vincent V Gallinat Jurgen J Garavan Hugh H Gowland Penny P Heinz Andreas A Lemaitre Herve H Martinot Jean-Luc JL Nees Frauke F Orfanos Dimitri Papadopoulos DP Pangelinan Melissa Marie MM Poustka Luise L Rietschel Marcella M Smolka Michael N MN Walter Henrik H Whelan Robert R Timpson Nic J NJ Schumann Gunter G Smith George Davey GD Pausova Zdenka Z Paus Tomáš T

JAMA psychiatry 20151001 10

<h4>Importance</h4>Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure.<h4>Objective</h4>To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia.<h4>Design, setting, and participants</h4>Observati ...[more]

PMID: 26308966

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Project description:The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

Project description:BACKGROUND AND AIMS:Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories from ages 12-30 years and perceived peer cannabis use at ages 12-17 years. DESIGN:Mixed-effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership and perceived peer cannabis use. SETTING:United States. PARTICIPANTS:From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1167 individuals aged 12-26 years at their baseline (i.e. first) interview. MEASUREMENTS:Key measurements included life-time cannabis use (yes/no), frequency of past 12-month cannabis use, maximum life-time frequency of cannabis use, cannabis use disorder (using DSM-5 criteria) and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (n = 162?082) genome-wide association study (GWAS) of cannabis use. FINDINGS:Three trajectories reflecting no/low (n = 844), moderate (n = 137) and high (n = 186) use were identified. PRS were significantly associated with trajectory membership [P = 0.002-0.006, maximum conditional R2 = 1.4%, odds ratios (ORs) = 1.40-1.49]. Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users [OR = 1.35, 95% confidence interval (CI) = 1.04, 1.75, P = 0.023]. Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR = 1.50-4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (P < 0.01). CONCLUSIONS:Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults.

Dataset Information

Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence.

Publications

Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence.

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