39 research outputs found

    Effect of 16P11.2 copy number variants on cognitive traits and brain structures

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    The 600kb 16p11.2 CNVs (breakpoints 4–5, 29.6-30.2 Mb-Hg19) are among the most frequent genetic risk factors for neurodevelopmental and psychiatric conditions: A 10-fold enrichment of deletions and duplications is observed in autism cohorts and a 10-fold enrichment of duplications in schizophrenia cohorts. Previous studies demonstrated “mirror” effects of both CNVs on body mass index and head circumference (deletion>control>duplication). However, the large global effect of brain size and the sample size of the two previous neuroimaging studies limited the interpretation of the analyses on regional brain structures, any estimate of the effect size, and the generalizability of the results across different ascertainments of the patients. In the first part of my Ph.D., I analyze structural magnetic resonance imaging (MRI) on 78 deletion carriers, 71 duplication carriers, and 212 controls. I show that both CNVs affect in a “mirror” way the volume and the cortical surface of the insula (Cohen’s d>1), whilst other brain regions are preferentially altered in either the deletion carriers (calcarine cortex and superior, middle, transverse temporal gyri, Cohen’s d>1) or the duplication carriers (caudate and hippocampus, Cohen’s d of 0.5 to 1). Results are generalizable across scanning sites, computational methods, age, sex, ascertainment for psychiatric disorders. They partially overlap with results of meta-analyses performed across psychiatric disorders. In the second part, I characterize the developmental trajectory of global brain metrics and regional brain structures in the 16p11.2 CNV carriers. I adapt a previously published longitudinal pipeline and normalizing method, derived from 339 typically developing individuals aged from 4.5 to 20 years old. From this population of reference, I Z-score our cross-sectional 16p11.2 dataset and show that all the brain alterations in the 16p11.2 carriers are already present at 4.5 years old and follow parallel trajectories to the controls. In summary, my results suggest that brain alterations, present in childhood and stable across adolescence and adulthood, are related to the risk conferred by the 16p11.2 CNVs, regardless of the carriers’ symptoms. Additional factors are therefore likely required for the development of psychiatric disorders. I highlight the relevance of studying genetic risk factors and mechanisms as a complement to groups defined by behavioral criteria. Further studies comparing multiple CNVs and monogenic conditions, from the earliest age, are required to understand the onset of neuroanatomical alterations and their overlap between different genetic risk factors for neurodevelopmental disorders. -- Les variations en nombre de copies (CNV), au locus 16p11.2 et d’une taille d’600kb (points de cassure 4–5, 29.6-30.2 Mb-Hg19) reprĂ©sentent un des facteurs de risque gĂ©nĂ©tique les plus frĂ©quents parmi les troubles psychiatriques : 10% d’enrichissement en dĂ©lĂ©tion et duplication pour les troubles du spectre autistique, 10% d’enrichissement en duplication pour la schizophrĂ©nie. Les effets « miroirs » des deux CNVs sur l’indice de masse corporelle et le pĂ©rimĂštre cranien ont dĂ©jĂ  Ă©tĂ© dĂ©montrĂ©s (dĂ©lĂ©tion>contrĂŽle>duplication). Cependant, les diffĂ©rences en taille de cerveau et les Ă©chantillons des deux prĂ©cĂ©dentes Ă©tudes de neuro- imagerie ont limitĂ© les analyses des rĂ©gions cĂ©rĂ©brales, l’estimation de la taille des effets, et la gĂ©nĂ©ralisation des rĂ©sultats selon les modes de recrutement des patients. Dans cette thĂšse, j’analyse les images par rĂ©sonance magnĂ©tique (IRM) de 78 porteurs de la dĂ©lĂ©tion, 71 porteurs de la duplication et 212 participants contrĂŽles. Je montre que les deux CNVs sont associĂ©es Ă  des diffĂ©rences « en miroir » du volume et de la surface corticale de l’insula (Cohen’s d>1), tandis que le cortex calcarin, les gyri temporaux supĂ©rieur, moyen et transverse sont prĂ©fĂ©rentiellement altĂ©rĂ©s par la dĂ©lĂ©tion (Cohen’s d>1), les noyaux caudĂ©s et l’hippocampe sont prĂ©fĂ©rentiellement altĂ©rĂ©s par la duplication (0.5<Cohen’s d<1). Les rĂ©sultats sont gĂ©nĂ©ralisables Ă  travers les differents sites d’IRM, les mĂ©thodes d’analyse computationnelle, les Ăąges, les sexes et les divers diagnostiques psychiatriques des patients. Les rĂ©sultats chevauchent partiellement ceux d’une mĂ©ta-analyse sur plusieurs diagnostiques psychiatriques. Dans un second temps, je caractĂ©rise la trajectoire dĂ©veloppementale de ces diffĂ©rences cĂ©rĂ©brales. J’adapte un pipeline longitunal et une mĂ©thode de normalisation dĂ©jĂ  publiĂ©s, construits Ă  partir de 339 participants contrĂŽles de 4.5 Ă  20 ans. Je calcule des Z-scores pour nos donnĂ©es transversales et montre que les diffĂ©rences cĂ©rĂ©brales liĂ©es aux CNVs sont dĂ©jĂ  prĂ©sentes Ă  4.5 ans, avec les mĂȘmes tailles d’effet et une trajectoire parallĂšle aux contrĂŽles. En rĂ©sumĂ©, mes rĂ©sultats suggĂšrent que les diffĂ©rences cĂ©rĂ©brales, prĂ©sentes dans la jeune enfance et stables Ă  l’adolescence et l’ñge adulte, sont liĂ©es au risque confĂ©rĂ© par les CNVs en 16p11.2, quelque soient les symptĂŽmes. Des facteurs additionnels sont probablement nĂ©cessaires pour le dĂ©veloppement de maladies psychiatriques. Je montre la pertinence d’étudier les facteurs de risque gĂ©nĂ©tiques en complĂ©ment des groupes de patients dĂ©finis sur des critĂšres comportementaux. Des Ă©tudes comparant diverses conditions gĂ©nĂ©tiques, dĂšs la naissance, sont nĂ©cessaires pour comprendre le dĂ©but et le chevauchement des diffĂ©rences neuro-anatomiques observĂ©es pour diffĂ©rents facteurs de risque gĂ©nĂ©tiques

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

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    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

    Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles

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    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD

    Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations

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    Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

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    IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P 100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits

    Examples of swing tasks.

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    <p>A: Internal Swing (pretending to drink). B: External Swing (pretending to read). Same legend as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178185#pone.0178185.g007" target="_blank">Fig 7</a>.</p

    Examples of spinning tasks.

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    <p>A: Unimanual. B: Bimanual. Each figure represents the evolution of the time forces on the faces of the object. Phases and vertical stippled lines: same legend as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178185#pone.0178185.g004" target="_blank">Fig 4</a>.</p
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