Publications by authors named "Tomáš Paus"

317 Publications

Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts.

Front Psychiatry 2021 20;12:645746. Epub 2021 Apr 20.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study ( = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) ( = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 ( < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in (p =0.042, OR = 0.73) and rs507961 in (p = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 () and rs507961 () remained significantly associated with positive AUDIT screens ( < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction ( = 0.006) involving rs484061 (), rs4963307 (), and rs7766029 () predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.
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http://dx.doi.org/10.3389/fpsyt.2021.645746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093566PMC
April 2021

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

Biol Psychiatry 2021 Jan 30. Epub 2021 Jan 30.

Centre for Population Neuroscience and Stratified Medicine, Institute for Science and Technology of Brain-Inspired Intelligence, Fudan University, Shanghai, China; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.

Background: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues.

Methods: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels.

Results: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%.

Conclusions: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.
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http://dx.doi.org/10.1016/j.biopsych.2021.01.011DOI Listing
January 2021

Orbitofrontal control of conduct problems? Evidence from healthy adolescents processing negative facial affect.

Eur Child Adolesc Psychiatry 2021 Apr 16. Epub 2021 Apr 16.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159, Mannheim, Germany.

Conduct problems (CP) in patients with disruptive behavior disorders have been linked to impaired prefrontal processing of negative facial affect compared to controls. However, it is unknown whether associations with prefrontal activity during affective face processing hold along the CP dimension in a healthy population sample, and how subcortical processing is affected. We measured functional brain responses during negative affective face processing in 1444 healthy adolescents [M = 14.39 years (SD = 0.40), 51.5% female] from the European IMAGEN multicenter study. To determine the effects of CP, we applied a two-step approach: (a) testing matched subgroups of low versus high CP, extending into the clinical range [N = 182 per group, M = 14.44 years, (SD = 0.41), 47.3% female] using analysis of variance, and (b) considering (non)linear effects along the CP dimension in the full sample and in the high CP group using multiple regression. We observed no significant cortical or subcortical effect of CP group on brain responses to negative facial affect. In the full sample, regression analyses revealed a significant linear increase of left orbitofrontal cortex (OFC) activity with increasing CP up to the clinical range. In the high CP group, a significant inverted u-shaped effect indicated that left OFC responses decreased again in individuals with high CP. Left OFC activity during negative affective processing which is increasing with CP and decreasing in the highest CP range may reflect on the importance of frontal control mechanisms that counteract the consequences of severe CP by facilitating higher social engagement and better evaluation of social content in adolescents.
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http://dx.doi.org/10.1007/s00787-021-01770-1DOI Listing
April 2021

Corrigendum to: Pubertal testosterone and the structure of the cerebral cortex in young men.

Cereb Cortex 2021 May;31(6):3164

Department of Psychology, University of Toronto, Toronto, ON M5S3G3, Canada.

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http://dx.doi.org/10.1093/cercor/bhab111DOI Listing
May 2021

Neuroimaging evidence for structural correlates in adolescents resilient to polysubstance use: A five-year follow-up study.

Eur Neuropsychopharmacol 2021 Mar 23;49:11-22. Epub 2021 Mar 23.

School of Psychology and Global Brain Health Institute, University College Dublin, Dublin, Ireland.

Early initiation of polysubstance use (PSU) is a strong predictor of subsequent addiction, however scarce individuals present resilience capacity. This neuroimaging study aimed to investigate structural correlates associated with cessation or reduction of PSU and determine the extent to which brain structural features accounted for this resilient outcome. Participants from a European community-based cohort self-reported their alcohol, tobacco and cannabis use frequency at ages 14, 16 and 19 and had neuroimaging sessions at ages 14 and 19. We included three groups in the study: the resilient-to-PSU participants showed PSU at 16 and/or 14 but no more at 19 (n = 18), the enduring polysubstance users at 19 displayed PSU continuation from 14 or 16 (n = 193) and the controls were abstinent or low drinking participants (n = 460). We conducted between-group comparisons of grey matter volumes on whole brain using voxel-based morphometry and regional fractional anisotropy using tract-based spatial statistics. Random-forests machine-learning approach generated individual-level PSU-behavior predictions based on personality and neuroimaging features. Adolescents resilient to PSU showed significant larger grey matter volumes in the bilateral cingulate gyrus compared with enduring polysubstance users and controls at ages 19 and 14 (p<0.05 corrected) but no difference in fractional anisotropy. The larger cingulate volumes and personality trait "openness to experience" were the best precursors of resilience to PSU. Early in adolescence, a larger cingulate gyrus differentiated adolescents resilient to PSU, and this feature was critical in predicting this outcome. This study encourages further research into the neurobiological bases of resilience to addictive behaviors.
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http://dx.doi.org/10.1016/j.euroneuro.2021.03.001DOI Listing
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 Mar 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Predicting depression onset in young people based on clinical, cognitive, environmental and neurobiological data.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 19. Epub 2021 Mar 19.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany.

Background: Adolescent onset of depression is associated with long-lasting negative consequences. Identifying adolescents at risk for developing depression would enable the monitoring of risk-factors and the development of early intervention strategies. Using machine learning to combine several risk factors from multiple modalities might allow prediction of depression onset at the individual level.

Methods: A subsample of a multi-site longitudinal study in adolescents, the IMAGEN study, was used to predict future (subthreshold) major depressive disorder (MDD) onset in healthy adolescents. Based on 2-year and 5-year follow-up data, participants were grouped into: 1) developing an MDD diagnosis or subthreshold MDD and 2) healthy controls. Baseline measurements of 145 variables from different modalities (clinical, cognitive, environmental and structural magnetic resonance imaging [MRI]) at age 14 were used as input to penalized logistic regression (with different levels of penalization) to predict depression onset in a training dataset (N=407). The features contributing highest to the prediction were validated in an independent hold-out sample (3 independent IMAGEN sites; N=137).

Results: The area under the receiver operating characteristics curve (AUROC) for predicting depression onset ranged between 0.70-0.72 in the training dataset. Baseline severity of depressive symptoms, female sex, neuroticism, stressful life events and surface area of the supramarginal gyrus contributed most to the predictive model and predicted onset of depression with an AUROC between 0.68-0.72 in the independent validation sample.

Conclusions: This study showed that depression onset in adolescents can be predicted based on a combination multimodal data of clinical, life events, personality traits, brain structure variables.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.005DOI Listing
March 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Pubertal Testosterone and Brain Response to Faces in Young Adulthood: An Interplay between Organizational and Activational Effects in Young Men.

J Neurosci 2021 Mar 15;41(13):2990-2999. Epub 2021 Feb 15.

Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada

According to the organizational-activational hypothesis, the organizational effects of testosterone during (prenatal) brain development moderate the activational effects of adult testosterone on behavior. Accumulating evidence supports the notion that adolescence is another period during which sex hormones organize the nervous system. Here we investigate how pubertal sex hormones moderate the activational effects of adult sex hormones on social cognition in humans. To do so, we recruited a sample of young men ( = 507; age, ∼19 years) from a longitudinal birth cohort and investigated whether testosterone exposure during adolescence (from 9 to 17 years of age) moderates the relation between current testosterone and brain response to faces in young adulthood, as assessed with functional magnetic resonance imaging (fMRI). Our results showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean fMRI response and functional connectivity (i.e., node strength). Specifically, in participants with low exposure to testosterone during puberty, we observed a positive relationship between current testosterone and the brain response to faces; this was not the case for participants with medium and high pubertal testosterone. Furthermore, we observed a stronger relationship between the brain response and current testosterone in parts of the angry-face network associated with (vs without) motion in the eye region of an observed (angry) face. We speculate that pubertal testosterone modulates the relationship between current testosterone and brain response to social cues carried by the eyes and signaling a potential threat. Accumulating evidence supports the organizational effects of pubertal testosterone, but the body of literature examining these effects on social cognition in humans is in its infancy. With a sample of young men from a longitudinal birth cohort, we showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean BOLD signal change and functional connectivity. Specifically, we observed a positive relationship between adult testosterone and the brain response to faces in participants with low exposure to testosterone during puberty, but not in participants with medium and high pubertal testosterone. Results of further analysis suggest that sensitivity to cues carried by the eyes might underlie the relationship between testosterone and brain response to faces, especially in the context of a potential threat.
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http://dx.doi.org/10.1523/JNEUROSCI.0190-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018886PMC
March 2021

Irregular sleep habits, regional grey matter volumes, and psychological functioning in adolescents.

PLoS One 2021 10;16(2):e0243720. Epub 2021 Feb 10.

National Institute of Health and Medical Research, INSERM U A10 "Trajectoires développementales & psychiatrie", University Paris-Saclay, Ecole Normale Supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France.

Changing sleep rhythms in adolescents often lead to sleep deficits and a delay in sleep timing between weekdays and weekends. The adolescent brain, and in particular the rapidly developing structures involved in emotional control, are vulnerable to external and internal factors. In our previous study in adolescents at age 14, we observed a strong relationship between weekend sleep schedules and regional medial prefrontal cortex grey matter volumes. Here, we aimed to assess whether this relationship remained in this group of adolescents of the general population at the age of 16 (n = 101; mean age 16.8 years; 55% girls). We further examined grey matter volumes in the hippocampi and the amygdalae, calculated with voxel-based morphometry. In addition, we investigated the relationships between sleep habits, assessed with self-reports, and regional grey matter volumes, and psychological functioning, assessed with the Strengths and Difficulties Questionnaire and tests on working memory and impulsivity. Later weekend wake-up times were associated with smaller grey matter volumes in the medial prefrontal cortex and the amygdalae, and greater weekend delays in wake-up time were associated with smaller grey matter volumes in the right hippocampus and amygdala. The medial prefrontal cortex region mediated the correlation between weekend wake up time and externalising symptoms. Paying attention to regular sleep habits during adolescence could act as a protective factor against the emergence of psychopathology via enabling favourable brain development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243720PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875363PMC
February 2021

Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults?

Schizophr Res 2021 Feb 23;228:271-279. Epub 2021 Jan 23.

Department of Developmental Psychology, Adapt Lab, Research Priority Area Yield, University of Amsterdam, Nieuwe Achtergracht 129-B, 1018 WS Amsterdam, the Netherlands.

Objective: To assess changes in cannabis use in young adults as a function of psychotic-like experiences.

Method: Participants were initially recruited at age 14 in high schools for the longitudinal IMAGEN study. All measures presented here were assessed at follow-ups at age 19 and at age 22, respectively. Perceived stress was only assessed once at age 22. Ever users of cannabis (N = 552) gave qualitative and quantitative information on cannabis use and psychotic-like experiences using the Community Assessment of Psychic Experiences (CAPE). Of those, nearly all n = 549 reported to have experienced at least one psychotic experience of any form at age 19.

Results: Mean cannabis use increased from age 19 to 22 and age of first use of cannabis was positively associated with a change in cannabis use between the two time points. Change in cannabis use was not significantly associated with psychotic-like experiences at age 19 or 22. In exploratory analysis, we observed a positive association between perceived stress and the experience of psychotic experiences at age 22.

Conclusion: Age of first use of cannabis influenced trajectories of young cannabis users with later onset leading to higher increase, whereas the frequency of psychotic-like experiences was not associated with a change in cannabis use. The observed association between perceived stress and psychotic-like experiences at age 22 emphasizes the importance of stress experiences in developing psychosis independent of cannabis use.
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http://dx.doi.org/10.1016/j.schres.2021.01.002DOI Listing
February 2021

Pubertal Testosterone and the Structure of the Cerebral Cortex in Young Men.

Cereb Cortex 2021 May;31(6):2812-2821

Department of Psychology, University of Toronto, Toronto, ON M5S3G3, Canada.

Adolescence is a period of brain maturation that may involve a second wave of organizational effects of sex steroids on the brain. Rodent studies suggest that, overall, organizational effects of gonadal steroid hormones decrease from the prenatal/perinatal period to adulthood. Here we used multimodal magnetic resonance imaging to investigate whether 1) testosterone exposure during adolescence (9-17 years) correlates with the structure of cerebral cortex in young men (n = 216, 19 years of age); 2) this relationship is modulated by the timing of testosterone surge during puberty. Our results showed that pubertal testosterone correlates with structural properties of the cerebral cortex, as captured by principal component analysis of T1 and T2 relaxation times, myelin water fraction, magnetization transfer ratio, fractional anisotropy and mean diffusivity. Many of the correlations between pubertal testosterone and the cortical structure were stronger in individuals with earlier (vs. later) testosterone surge. We also demonstrated that the strength of the relationship between pubertal testosterone and cortical structure across the cerebral cortex varies as a function of inter-regional profiles of gene expression specific to dendrites, axonal cytoskeleton, and myelin. This finding suggests that the cellular substrate underlying the relationships between pubertal testosterone and cerebral cortex involves both dendritic arbor and axon.
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http://dx.doi.org/10.1093/cercor/bhaa389DOI Listing
May 2021

Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.
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http://dx.doi.org/10.1038/s41380-020-00985-zDOI Listing
January 2021

Epigenetic clock as a correlate of anxiety.

Neuroimage Clin 2020 6;28:102458. Epub 2020 Oct 6.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Rd, East York, Toronto, ON M4G1R8, Canada; Departments of Psychology and Psychiatry, University of Toronto, 100 St. George Street, Toronto, ON M5S3G3, Canada.

DNA methylation changes consistently throughout life and age-dependent alterations in DNA methylation can be used to estimate one's epigenetic age. Post-mortem studies revealed higher epigenetic age in brains of patients with major depressive disorder, as compared with controls. Since MDD is highly correlated with anxiety, we hypothesized that symptoms of anxiety, as well as lower volume of grey matter (GM) in depression-related cortical regions, will be associated with faster epigenetic clock in a community-based sample of young adults. Participants included 88 young adults (53% men; 23-24 years of age) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) who participated in its neuroimaging follow-up and provided saliva samples for epigenetic analysis. Epigenetic age was calculated according to Horvath (Horvath, 2013). Women had slower epigenetic clock than men (Cohen's d = 0.48). In women (but not men), slower epigenetic clock was associated with less symptoms of anxiety. In the brain, women (but not men) with slower epigenetic clock had greater GM volume in the cerebral cortex (brain size-corrected; R = 0.07). Lobe-specific analyses showed that in women (but not men), slower epigenetic clock was associated with greater GM volume in frontal lobe (R = 0.16), and that GM volume in frontal lobe mediated the relationship between the speed of epigenetic clock and anxiety trait (ab = 0.15, SE = 0.15, 95% CI [0.007; 0.369]). These findings were not replicated, however, in a community-based sample of adolescents (n = 129; 49% men; 12-19 years of age), possibly due to the different method of tissue collection (blood vs. saliva) or additional sources of variability in the cohort of adolescents (puberty stages, socioeconomic status, prenatal exposure to maternal smoking during pregnancy).
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http://dx.doi.org/10.1016/j.nicl.2020.102458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585143PMC
October 2020

SARS-CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking.

Am J Hypertens 2021 04;34(4):367-376

Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada.

Background: Angiotensin-converting enzyme 2 (ACE2) has been identified as the entry receptor for coronaviruses into human cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Since hypertension (HT) is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and HT in interaction with specific pre-existing conditions known to be associated with COVID-19 severity.

Methods: Genetic analysis of ACE2 gene was conducted in French-Canadian (FC) and British populations.

Results: In FC individuals, the T allele of the single nucleotide polymorphism rs2074192 of ACE2 gene was a risk factor for HT in adult obese males [odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.06-1.83)] and even more so in obese males who smoked (OR = 1.67, CI: 1.24-2.55), but not in lean males, non-smoker males or females. The T allele was significantly associated with severity of HT and with earlier penetrance of HT in obese smoking males. Significant interaction between the T allele and obesity was present in both sexes. The association of ACE2 (rs233575) genotype with blood pressure was also seen in adolescents but the interaction with obesity was present only in females. Several variants in ACE2 gene were found to be associated with HT in obese, smoking males in British individuals of the UK Biobank. In addition, we observed more severe outcomes to COVID-19 in association with ACE2 risk alleles in obese, smoking males.

Conclusions: This is the first report that ACE2 variants are associated with earlier penetrance and more severe HT and with more severe outcomes of COVID-19 in obese smoking males.
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http://dx.doi.org/10.1093/ajh/hpaa223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799248PMC
April 2021

Consensus Parameter: Research Methodologies to Evaluate Neurodevelopmental Effects of Pubertal Suppression in Transgender Youth.

Transgend Health 2020 11;5(4):246-257. Epub 2020 Dec 11.

Center for Biobehavioral Health, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.

Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender identity. Preliminary evidence suggests pubertal suppression improves mental health functioning. Given the widespread changes in brain and cognition that occur during puberty, a critical question is whether this treatment impacts neurodevelopment. A Delphi consensus procedure engaged 24 international experts in neurodevelopment, gender development, puberty/adolescence, neuroendocrinology, and statistics/psychometrics to identify priority research methodologies to address the empirical question: is pubertal suppression treatment associated with real-world neurocognitive sequelae? Recommended study approaches reaching 80% consensus were included in the consensus parameter. The Delphi procedure identified 160 initial expert recommendations, 44 of which ultimately achieved consensus. Consensus study design elements include the following: a minimum of three measurement time points, pubertal staging at baseline, statistical modeling of sex in analyses, use of analytic approaches that account for heterogeneity, and use of multiple comparison groups to minimize the limitations of any one group. Consensus study comparison groups include untreated transgender youth matched on pubertal stage, cisgender (i.e., gender congruent) youth matched on pubertal stage, and an independent sample from a large-scale youth development database. The consensus domains for assessment includes: mental health, executive function/cognitive control, and social awareness/functioning. An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth.
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http://dx.doi.org/10.1089/trgh.2020.0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759272PMC
December 2020

Adiposity-related insulin resistance and thickness of the cerebral cortex in middle-aged adults.

J Neuroendocrinol 2020 12;32(12):e12921

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

The thickness of the cerebral cortex decreases with ageing. Recent research suggests that obesity and type 2 diabetes mellitus may accelerate this cortical thinning, and that obesity-related insulin resistance may be a shared mechanistic pathway. Ageing of the cerebral cortex demonstrates sex-specific trajectories, with a gradual shift towards accelerated thinning beginning in midlife. Here, we investigated whether adiposity-related insulin resistance is associated with lower thickness of the human cerebral cortex in a community-based sample of middle-aged adults. We studied 533 adult participants (36-65 years) from the Saguenay Youth Study. Adiposity was assessed with bioimpedance, and insulin resistance was evaluated from a fasting blood sample with the homeostatic model assessment of insulin resistance (HOMA-IR). Associations between adiposity-related insulin resistance (adiposity/IR) and cortical thickness were assessed with linear models, separately in males and females younger or older than 50 years. Potential biological underpinnings were investigated with virtual histology. Adiposity/IR was associated with lower cortical thickness in females older than 50 years but not in males or younger females. The strength of the association varied across the cerebral cortex, with regions of the lateral frontal and parietal cortices and the superior temporal cortex demonstrating most pronounced thinning. Based on virtual histology, adiposity/IR-related cortical thinning may involve neurones, astrocytes, oligodendrocytes and ependymal cells acting so that they lower the cortical potential for synaptogenesis, formation of dendritic spines, production of extracellular matrix and myelination. Adiposity-related insulin resistance is associated with lower cortical thickness in middle-aged women older than 50 years. This aspect of thinning may involve neuronal and glial cells in a way that lowers the capacity of the cerebral cortex for neuronal plasticity and maintenance of myelination.
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http://dx.doi.org/10.1111/jne.12921DOI Listing
December 2020

Cellular correlates of cortical thinning throughout the lifespan.

Sci Rep 2020 12 11;10(1):21803. Epub 2020 Dec 11.

Centre for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Pb. 1094 Blindern, 0317, Oslo, Norway.

Cortical thinning occurs throughout the entire life and extends to late-life neurodegeneration, yet the neurobiological substrates are poorly understood. Here, we used a virtual-histology technique and gene expression data from the Allen Human Brain Atlas to compare the regional profiles of longitudinal cortical thinning through life (4004 magnetic resonance images [MRIs]) with those of gene expression for several neuronal and non-neuronal cell types. The results were replicated in three independent datasets. We found that inter-regional profiles of cortical thinning related to expression profiles for marker genes of CA1 pyramidal cells, astrocytes and, microglia during development and in aging. During the two stages of life, the relationships went in opposite directions: greater gene expression related to less thinning in development and vice versa in aging. The association between cortical thinning and cell-specific gene expression was also present in mild cognitive impairment and Alzheimer's Disease. These findings suggest a role of astrocytes and microglia in promoting and supporting neuronal growth and dendritic structures through life that affects cortical thickness during development, aging, and neurodegeneration. Overall, the findings contribute to our understanding of the neurobiology underlying variations in MRI-derived estimates of cortical thinning through life and late-life disease.
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http://dx.doi.org/10.1038/s41598-020-78471-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732849PMC
December 2020

Association of Genetic and Phenotypic Assessments With Onset of Disordered Eating Behaviors and Comorbid Mental Health Problems Among Adolescents.

JAMA Netw Open 2020 12 1;3(12):e2026874. Epub 2020 Dec 1.

Technische Universität Dresden, Faculty of Medicine Carl Gustav Carus, Department of Psychiatry and Psychotherapy, Section of Systems Neuroscience, Dresden, Germany.

Importance: Eating disorders are serious mental disorders with increasing prevalence. Without early identification and treatment, eating disorders may run a long-term course.

Objective: To characterize any associations among disordered eating behaviors (DEBs) and other mental health disorders and to identify early associations with the development of symptoms over time.

Design, Setting, And Participants: This multicenter, population-based, longitudinal cohort study used data from baseline (collected in 2010), follow-up 1 (collected in 2012), and follow-up 2 (collected in 2015) of the IMAGEN Study, which included adolescents recruited from 8 European sites. The present study assessed data from 1623 healthy adolescents, aged 14 years at baseline, recruited from high schools. Data analyses were performed from January 2018 to September 2019.

Main Outcomes And Measures: Body mass index (BMI), mental health symptoms, substance use behaviors, and personality variables were investigated as time-varying associations of DEBs (dieting, binge eating, and purging) or change in BMI over time. Polygenic risk scores were calculated to investigate genetic contributions associated with BMI, attention-deficit/hyperactivity disorder (ADHD) and neuroticism to DEBs.

Results: In this cohort study of 1623 adolescents (829 girls [51.1%]) recruited at a mean (SD) age of 14.5 (0.4) years and followed up at ages 16 and 19 years, 278 adolescents (17.1%) reported binge eating, 334 adolescents (20.6%) reported purging, and 356 adolescents (21.9%) reported dieting at 14, 16, or 19 years. Among the precursors of DEBs, high BMI was associated with future dieting (OR, 3.44; 95% CI, 2.09-5.65). High levels of neuroticism (OR, 1.04; 95% CI, 1.01-1.06), conduct problems (OR, 1.41; 95% CI, 1.17-1.69), and deliberate self-harm (OR, 2.18; 95% CI, 1.37-3.45) were associated with future binge eating. Low agreeableness (OR, 0.95; 95% CI, 0.92-0.97), deliberate self-harm (OR, 2.59; 95% CI, 1.69-3.95), conduct problems (OR, 1.42; 95% CI, 1.20-1.68), alcohol misuse (OR, 1.31; 95% CI, 1.10-1.54), and drug abuse (OR, 2.91; 95% CI, 1.78-4.74) were associated with future purging. Polygenetic risk scores for BMI were associated with dieting (at 14 years: OR, 1.27; lower bound 95% CI, 1.08; at 16 years: OR, 1.38; lower bound 95% CI, 1.17); ADHD, with purging (at 16 years: OR, 1.25; lower bound 95% CI, 1.08; at 19 years, OR, 1.23; lower bound 95% CI, 1.06); and neuroticism, with binge eating (at 14 years: OR, 1.32; lower bound 95% CI, 1.11; at 16 years: OR, 1.24; lower bound 95% CI, 1.06), highlighting distinct etiologic overlaps between these traits. The DEBs predated other mental health problems, with dieting at 14 years associated with future symptoms of depression (OR, 2.53; 95% CI, 1.56-4.10), generalized anxiety (OR, 2.27; 95% CI, 1.14-4.51), deliberate self-harm (OR, 2.10; 95% CI, 1.51-4.24), emotional problems (OR, 1.24; 95% CI, 1.08-1.43), and smoking (OR, 2.16; 95% CI, 1.36-3.48). Purging at 14 years was also associated with future depression (OR, 2.87; 95% CI, 1.69-5.01) and anxiety (OR, 2.48; 95% CI, 1.49-4.12) symptoms.

Conclusions And Relevance: The findings of this study delineate temporal associations and shared etiologies among DEBs and other mental health disorders and emphasize the potential of genetic and phenotypical assessments of obesity, behavioral disorders, and neuroticism to improve early and differential diagnosis of eating disorders.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.26874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711322PMC
December 2020

Donor-Specific Transcriptomic Analysis of Alzheimer's Disease-Associated Hypometabolism Highlights a Unique Donor, Ribosomal Proteins and Microglia.

eNeuro 2020 Nov-Dec;7(6). Epub 2020 Nov 24.

Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1L8, Canada

Alzheimer's disease (AD) starts decades before clinical symptoms appear. Low-glucose utilization in regions of the cerebral cortex marks early AD. To identify these regions, we conducted a voxel-wise meta-analysis of previous studies conducted with positron emission tomography that compared AD patients with healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, and middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes that show spatial correlation across the cerebral cortex between their expression and this hypometabolism. Of the six brains in the Atlas, one demonstrated a strong spatial correlation between gene expression and hypometabolism. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when comparing this donor's brain with the other five donors. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which encode primarily cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes increases progressively across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization reveals a link to AD-associated hypometabolism that may be relevant to preclinical stages of AD.
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http://dx.doi.org/10.1523/ENEURO.0255-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772516PMC
November 2020

Reward Versus Nonreward Sensitivity of the Medial Versus Lateral Orbitofrontal Cortex Relates to the Severity of Depressive Symptoms.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 10;6(3):259-269. Epub 2020 Sep 10.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany.

Background: The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms.

Methods: Activations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14.

Results: The medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003).

Conclusions: Activations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores.
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http://dx.doi.org/10.1016/j.bpsc.2020.08.017DOI Listing
March 2021

Sex continuum in the brain and body during adolescence and psychological traits.

Nat Hum Behav 2021 02 2;5(2):265-272. Epub 2020 Nov 2.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.

Many traits of the brain and body show marked sex differences, but the distributions of their values overlap substantially between the two sexes. To investigate variations associated with biological sex, beyond binary differences, we create continuous sex scores capturing the inter-individual variability in phenotypes. In an adolescent cohort (n = 1,029; 533 females), we have generated three sex scores based on brain-body traits: 'overall' (48 traits), 'pubertal' (26 traits) and 'non-pubertal' (22 traits). We then conducted sex-stratified multiple linear regressions (adjusting for age) using sex scores to test associations with sex hormones, personality traits and internalizing-externalizing behaviour. Higher sex scores (that is, greater 'femaleness') were associated with lower testosterone in males only, as well as lower extraversion, higher internalizing and lower externalizing in both sexes. The associations with testosterone, internalizing and externalizing were driven by pubertal sex scores, underscoring the importance of adolescence in shaping within-sex individual variability.
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http://dx.doi.org/10.1038/s41562-020-00968-8DOI Listing
February 2021

Population neuroimaging: generation of a comprehensive data resource within the ALSPAC pregnancy and birth cohort.

Wellcome Open Res 2020 28;5:203. Epub 2020 Aug 28.

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, BS8 2BN, UK.

Neuroimaging offers a valuable insight into human brain development by allowing assessment of structure, connectivity and function. Multimodal neuroimaging data have been obtained as part of three sub-studies within the Avon Longitudinal Study of Parents and Children, a prospective multigenerational pregnancy and birth cohort based in the United Kingdom. Brain imaging data were acquired when offspring were between 18 and 24 years of age, and included acquisition of structural, functional and magnetization transfer magnetic resonance, diffusion tensor, and magnetoencephalography imaging. This resource provides a unique opportunity to combine neuroimaging data with extensive phenotypic and genotypic measures from participants, their mothers, and fathers.
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http://dx.doi.org/10.12688/wellcomeopenres.16060.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531050PMC
August 2020

Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study.

J Am Acad Child Adolesc Psychiatry 2021 May 1;60(5):623-636. Epub 2020 Oct 1.

Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

Objective: It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences.

Method: Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting.

Results: From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p < .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p > .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008).

Conclusion: These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.
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http://dx.doi.org/10.1016/j.jaac.2020.08.443DOI Listing
May 2021

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Effect Sizes of Deletions and Duplications on Autism Risk Across the Genome.

Am J Psychiatry 2021 01 11;178(1):87-98. Epub 2020 Sep 11.

Université de Montréal, Montreal (Douard, Zeribi, Schramm, Tamer, Loum, Nowak, Lord, Moreau, Huguet, Jacquemont); UHC Sainte-Justine Research Center, Montreal (Douard, Zeribi, Schramm, Tamer, Loum, Nowak, Saci, Lord, Rodríguez-Herreros, Jean-Louis, Moreau, Huguet, Jacquemont); Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal (Schramm, Greenwood); Sensory-Motor Laboratory, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland (Rodríguez-Herreros); Department of Forensic and Neurodevelopmental Sciences (Loth) and Center for Population Neuroscience and Stratified Medicine (Schumann), Institute of Psychiatry, Psychology, and Neuroscience, King's College London; Hospital for Sick Children and Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto (Pausova); Departments of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal (Elsabbagh); Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia (Almasy); Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston (Glahn); Human Genetics and Cognitive Functions, Institut Pasteur, Université de Paris, Paris (Bourgeron); Département de Sciences de la Décision, HEC Montreal, Montreal (Labbe); Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto (Paus); Departments of Psychology and Psychiatry, University of Toronto, Toronto (Paus); Centre de Recherche de CIUSSS-NIM, Montreal (Mottron); Département de Psychiatrie, Université de Montréal, Montreal (Mottron); Department of Epidemiology, Biostatistics, and Occupational Health, Gerald Bronfman Department of Oncology, and Department of Human Genetics, McGill University, Montreal (Greenwood).

Objective: Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, levels of autism risk conferred by most rare CNVs remain unknown. The authors recently developed statistical models to estimate the effect size on IQ of all CNVs, including undocumented ones. In this study, the authors extended this model to autism susceptibility.

Methods: The authors identified CNVs in two autism populations (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models were used to test nine quantitative variables associated with genes encompassed in CNVs to explain their effects on IQ, autism susceptibility, and behavioral domains.

Results: The "probability of being loss-of-function intolerant" (pLI) best explains the effect of CNVs on IQ and autism risk. Deleting 1 point of pLI decreases IQ by 2.6 points in autism and unselected populations. The effect of duplications on IQ is threefold smaller. Autism susceptibility increases when deleting or duplicating any point of pLI. This is true for individuals with high or low IQ and after removing de novo and known recurrent neuropsychiatric CNVs. When CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behavior, and phonological memory, whereas both equally affect motor skills.

Conclusions: Autism risk conferred by duplications is less influenced by IQ compared with deletions. The model applied in this study, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk and IQ loss. These models will help to interpret CNVs identified in the clinic.
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http://dx.doi.org/10.1176/appi.ajp.2020.19080834DOI Listing
January 2021

Orbitofrontal cortex volume links polygenic risk for smoking with tobacco use in healthy adolescents.

Psychol Med 2020 Sep 3:1-8. Epub 2020 Sep 3.

Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, 95 East Zhongguancun Road, Beijing, 100190, China.

Background: Tobacco smoking remains one of the leading causes of preventable illness and death and is heritable with complex underpinnings. Converging evidence suggests a contribution of the polygenic risk for smoking to the use of tobacco and other substances. Yet, the underlying brain mechanisms between the genetic risk and tobacco smoking remain poorly understood.

Methods: Genomic, neuroimaging, and self-report data were acquired from a large cohort of adolescents from the IMAGEN study (a European multicenter study). Polygenic risk scores (PGRS) for smoking were calculated based on a genome-wide association study meta-analysis conducted by the Tobacco and Genetics Consortium. We examined the interrelationships among the genetic risk for smoking initiation, brain structure, and the number of occasions of tobacco use.

Results: A higher smoking PGRS was significantly associated with both an increased number of occasions of tobacco use and smaller cortical volume of the right orbitofrontal cortex (OFC). Furthermore, reduced cortical volume within this cluster correlated with greater tobacco use. A subsequent path analysis suggested that the cortical volume within this cluster partially mediated the association between the genetic risk for smoking and the number of occasions of tobacco use.

Conclusions: Our data provide the first evidence for the involvement of the OFC in the relationship between smoking PGRS and tobacco use. Future studies of the molecular mechanisms underlying tobacco smoking should consider the mediation effect of the related neural structure.
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http://dx.doi.org/10.1017/S0033291720002962DOI Listing
September 2020

Neural Correlates of Adolescent Irritability and Its Comorbidity With Psychiatric Disorders.

J Am Acad Child Adolesc Psychiatry 2020 12 27;59(12):1371-1379. Epub 2020 Aug 27.

Vermont Center on Behavior and Health, University of Vermont, Burlington.

Objective: Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. We examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2,024 14-year-old adolescents from 5 European countries.

Method: The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder, major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural magnetic resonance imaging was examined using whole-brain voxel-based morphometry analysis, and functional magnetic resonance imaging was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses.

Results: Whole-brain voxelwise analysis showed that adolescent irritable mood was associated with less gray matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p < .05). Structural equation models suggested that part of the observed smaller gray matter volume was exclusively driven by irritability separate from direct relationships between generalized anxiety disorder (or attention-deficit/hyperactivity disorder, major depressive disorder, or oppositional defiant disorder) and gray matter volume.

Conclusion: This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.
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http://dx.doi.org/10.1016/j.jaac.2019.11.028DOI Listing
December 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Thickness of the cerebral cortex shows positive association with blood levels of triacylglycerols carrying 18-carbon fatty acids.

Commun Biol 2020 Aug 20;3(1):456. Epub 2020 Aug 20.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Perturbations in fatty acid (FA) metabolism as well as thinning of the cerebral cortex have been associated with cognitive decline in the elderly. Predominant FAs in the brain are docosahexaenoic acid (DHA) and arachidonic acid (ARA). Approximately 2-8% of esterified DHA and 3-5% of esterified ARA in the brain are replaced daily. DHA and ARA are derivatives of 18-carbon essential FAs, α-linolenic acid and linoleic acid, that must be imported into the brain from the circulation. In blood, FAs are primarily transported in triacylglycerols (TAGs) from which they can be released at the blood-brain-barrier and transported inside the brain. We show that circulating levels of TAGs carrying 18-carbon FAs are positively associated with cortical thickness in middle-aged adults. These associations are stronger in cortical regions with higher expression of genes regulating long-chain FA metabolism and cellular membranes, and cortical thickness in the same regions may be related to cognitive performance.
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http://dx.doi.org/10.1038/s42003-020-01189-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441395PMC
August 2020