Publications by authors named "Thomas Bourgeron"

131 Publications

The meaning of significant mean group differences for biomarker discovery.

PLoS Comput Biol 2021 Nov 18;17(11):e1009477. Epub 2021 Nov 18.

Mila-Quebec Artificial Intelligence Institute, Montreal, Canada.

Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between "cases" and "controls," which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research-autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen's d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the "on average" when summarising their findings in their abstracts ("autistic people have deficits in X"), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers.
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http://dx.doi.org/10.1371/journal.pcbi.1009477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601419PMC
November 2021

A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder.

NPJ Genom Med 2021 Nov 4;6(1):91. Epub 2021 Nov 4.

Service de Génétique clinique, CH de Chambéry, Chambéry, France.

Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.
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http://dx.doi.org/10.1038/s41525-021-00254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568906PMC
November 2021

LMT USV Toolbox, a Novel Methodological Approach to Place Mouse Ultrasonic Vocalizations in Their Behavioral Contexts-A Study in Female and Male C57BL/6J Mice and in Mutant Females.

Front Behav Neurosci 2021 13;15:735920. Epub 2021 Oct 13.

Human Genetics and Cognitive Functions, Institut Pasteur, UMR 3571 CNRS, Université de Paris, Paris, France.

Ultrasonic vocalizations (USVs) are used as a phenotypic marker in mouse models of neuropsychiatric disorders. Nevertheless, current methodologies still require time-consuming manual input or sound recordings clean of any background noise. We developed a method to overcome these two restraints to boost knowledge on mouse USVs. The methods are freely available and the USV analysis runs online at https://usv.pasteur.cloud. As little is currently known about usage and structure of ultrasonic vocalizations during social interactions over the long-term and in unconstrained context, we investigated mouse spontaneous communication by coupling the analysis of USVs with automatic labeling of behaviors. We continuously recorded during 3 days undisturbed interactions of same-sex pairs of C57BL/6J sexually naive males and females at 5 weeks and 3 and 7 months of age. In same-sex interactions, we observed robust differences between males and females in the amount of USVs produced, in the acoustic structure and in the contexts of emission. The context-specific acoustic variations emerged with increasing age. The emission of USVs also reflected a high level of excitement during social interactions. We finally highlighted the importance of studying long-term spontaneous communication by investigating female mice lacking , a synaptic protein associated with autism. While the previous short-time constrained investigations could not detect USV emission abnormalities, our analysis revealed robust differences in the usage and structure of the USVs emitted by mutant mice compared to wild-type female pairs.
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http://dx.doi.org/10.3389/fnbeh.2021.735920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548730PMC
October 2021

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder.

Am J Psychiatry 2021 Sep 10:appiajp202120050630. Epub 2021 Sep 10.

Department of Child and Adolescent Psychiatry, University Hospital, Goethe University, Frankfurt am Main, Germany (Ecker, Bletsch, Mann, Schaefer, Yousaf, Chiocchetti, Bast, Freitag).

Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions.

Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features.

Results: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.

Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
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http://dx.doi.org/10.1176/appi.ajp.2021.20050630DOI Listing
September 2021

Discriminant value of repetitive behaviors in families with autism spectrum disorder and obsessional compulsive disorder probands.

Autism Res 2021 11 19;14(11):2373-2382. Epub 2021 Jul 19.

Department of Child and Adolescent Psychiatry, Robert Debré Hospital, APHP, Paris, France.

Repetitive behaviors (RB) represent a wide spectrum of symptoms ranging from sensory-motor stereotypies to complex cognitive rituals, frequently dichotomized as low- and high-order sub-groups of symptoms. Even though these subgroups are considered as phenomenologically distinct in autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD), brain imaging and genetic studies suggest that they have common mechanisms and pathways. This discrepancy may be explained by the frequent intellectual disability reported in ASD, which blurs the RB expressivity. Given the high heritability of RB, that is, the diversity of symptoms expressed in the relatives are dependent on those expressed in their probands, we hypothesize that if RB expressed in ASD or OCD are two distinct entities, then the RB expressed in relatives will also reflect these two dimensions. We thus conduct a linear discriminant analysis on RB in both the relatives of probands with ASD and OCD and subjects from the general population (n = 1023). The discriminant analysis results in a classification of 81.1% of the controls (p < 10 ), but poorly differentiated the ASD and OCD relatives (≈46%). The stepwise analysis reveals that five symptoms attributed to high-order RB and two related to low-order RB (including hypersensitivity) are the most discriminant. Our results support the idea that the difference of RB patterns in the relatives is mild compared with the distribution of symptoms in controls. Our findings reinforce the evidence of a common biological pattern of RB both in ASD and OCD but with minor differences, specific to each of these two neuro-developmental disorders. LAY SUMMARY: Repetitive behaviors (RB), a key symptom in the classification of both OCD and ASD, are phenomenologically considered as distinct in the two disorders, which is in contrast with brain imaging studies describing a common neural circuit. Intellectual disability, which is frequently associated with ASD, makes RB in ASD more difficult to understand as it affects the expression of the RB symptoms. To avoid this bias, we propose to consider the familial aggregation in ASD and OCD by exploring RB in the first-degree relatives of ASD and OCD. Our results highlight the existence of RB expressed in relatives compared to the general population, with a common pattern of symptoms in relatives of both ASD and OCD but also minor differences, specific to each of these two neuro-developmental disorders.
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http://dx.doi.org/10.1002/aur.2570DOI Listing
November 2021

Testosterone Increases the Emission of Ultrasonic Vocalizations With Different Acoustic Characteristics in Mice.

Front Psychol 2021 25;12:680176. Epub 2021 Jun 25.

Department of Animal Science and Biotechnology, School of Veterinary Medicine, Azabu University, Sagamihara, Japan.

Testosterone masculinizes male sexual behavior through an organizational and activational effects. We previously reported that the emission of ultrasonic vocalizations (USVs) in male mice was dependent on the organizational effects of testosterone; females treated with testosterone in the perinatal and peripubertal periods, but not in adults, had increased USV emissions compared to males. Recently, it was revealed that male USVs have various acoustic characteristics and these variations were related to behavioral interactions with other mice. In this regard, the detailed acoustic characteristic changes induced by testosterone have not been fully elucidated. Here, we revealed that testosterone administered to female and male mice modulated the acoustic characteristics of USVs. There was no clear difference in acoustic characteristics between males and females. Call frequencies were higher in testosterone propionate (TP)-treated males and females compared to control males and females. When the calls were classified into nine types, there was also no distinctive difference between males and females, but TP increased the number of calls with a high frequency, and decreased the number of calls with a low frequency and short duration. The transition analysis by call type revealed that even though there was no statistically significant difference, TP-treated males and females had a similar pattern of transition to control males and females, respectively. Collectively, these results suggest that testosterone treatment can enhance the emission of USVs both in male and female, but the acoustic characteristics of TP-treated females were not the same as those of intact males.
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http://dx.doi.org/10.3389/fpsyg.2021.680176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267093PMC
June 2021

Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry.

Commun Biol 2021 05 14;4(1):574. Epub 2021 May 14.

Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland.

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97-99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.
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http://dx.doi.org/10.1038/s42003-021-02015-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121854PMC
May 2021

Operative list of genes associated with autism and neurodevelopmental disorders based on database review.

Mol Cell Neurosci 2021 06 29;113:103623. Epub 2021 Apr 29.

Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, F-75015 Paris, France. Electronic address:

The genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated with conditions such as intellectual disability and autism. The functional roles of these genes are currently studied to uncover the biological mechanisms influencing the clinical outcome of the mutation carriers. To integrate the data, several databases and curated gene lists have been generated. Here, we provide an overview of the main databases focusing on the genetics of NDD, that are widely used by the medical and scientific communities, and extract a list of high confidence NDD genes (HC-NDD). This gene set can be used as a first filter for interpreting large scale omics dataset or for diagnostic purposes. Overall HC-NDD genes (N = 1,586) are expressed at very early stages of fetal brain development and enriched in several biological pathways such as chromosome organization, cell cycle, metabolism and synaptic function. Among those HC-NDD genes, 204 (12,9%) are listed in the synaptic gene ontology SynGO and are enriched in genes expressed after birth in the cerebellum and the cortex of the human brain. Finally, we point at several limitations regarding the relatively poor standardized information available, especially on the carriers of the mutations. Progress on the phenotypic characterization and genetic profiling of the carriers will be crucial to improve our knowledge on the biological mechanisms and on risk and protective factors for NDD.
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http://dx.doi.org/10.1016/j.mcn.2021.103623DOI Listing
June 2021

Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition.

Genome Res 2021 03 13;31(3):484-496. Epub 2021 Jan 13.

Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris 75015, France.

The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes ( = 11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein-coding genome with recent data sets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism. Among those, a number of DNA damage response genes associated with microcephaly in humans such as , , , and show strong signs of positive selection and might have played a role in human brain size expansion during primate evolution. We also showed that cerebellum granule neurons express a set of genes also presenting signatures of positive selection and that may have contributed to the emergence of fine motor skills and social cognition in humans. This resource is available online and can be used to estimate evolutionary constraints acting on a set of genes and to explore their relative contributions to human traits.
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http://dx.doi.org/10.1101/gr.262113.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919455PMC
March 2021

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

Mol Psychiatry 2021 06 7;26(6):2663-2676. 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
June 2021

Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders.

Transl Psychiatry 2021 01 7;11(1):23. Epub 2021 Jan 7.

Service de Biochimie et Biologie Moléculaire, INSERM U942, Hôpital Lariboisière, AP-HP, Paris, France.

Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD-an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparan-sulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.
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http://dx.doi.org/10.1038/s41398-020-01125-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791095PMC
January 2021

Mass-spectrometry analysis of the human pineal proteome during night and day and in autism.

J Pineal Res 2021 Apr 11;70(3):e12713. Epub 2021 Jan 11.

Human Genetics and Cognitive Functions, Institut Pasteur, UMR 3571 CNRS, University Paris Diderot, Paris, France.

The human pineal gland regulates day-night dynamics of multiple physiological processes, especially through the secretion of melatonin. Using mass-spectrometry-based proteomics and dedicated analysis tools, we identify proteins in the human pineal gland and analyze systematically their variation throughout the day and compare these changes in the pineal proteome between control specimens and donors diagnosed with autism. Results reveal diverse regulated clusters of proteins with, among others, catabolic carbohydrate process and cytoplasmic membrane-bounded vesicle-related proteins differing between day and night and/or control versus autism pineal glands. These data show novel and unexpected processes happening in the human pineal gland during the day/night rhythm as well as specific differences between autism donor pineal glands and those from controls.
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http://dx.doi.org/10.1111/jpi.12713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047921PMC
April 2021

Interactive Psychometrics for Autism With the Human Dynamic Clamp: Interpersonal Synchrony From Sensorimotor to Sociocognitive Domains.

Front Psychiatry 2020 26;11:510366. Epub 2020 Nov 26.

Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France.

The human dynamic clamp (HDC) is a human-machine interface designed on the basis of coordination dynamics for studying realistic social interaction under controlled and reproducible conditions. Here, we propose to probe the validity of the HDC as a psychometric instrument for quantifying social abilities in children with autism spectrum disorder (ASD) and neurotypical development. To study interpersonal synchrony with the HDC, we derived five standardized scores following a gradient from sensorimotor and motor to higher sociocognitive skills in a sample of 155 individuals (113 participants with ASD, 42 typically developing participants; aged 5 to 25 years; IQ > 70). Regression analyses were performed using normative modeling on global scores according to four subconditions (HDC behavior "cooperative/competitive," human task "in-phase/anti-phase," diagnosis, and age at inclusion). Children with ASD had lower scores than controls for motor skills. HDC motor coordination scores were the best candidates for stratification and diagnostic biomarkers according to exploratory analyses of hierarchical clustering and multivariate classification. Independently of phenotype, sociocognitive skills increased with developmental age while being affected by the ongoing task and HDC behavior. Weaker performance in ASD for motor skills suggests the convergent validity of the HDC for evaluating social interaction. Results provided additional evidence of a relationship between sensorimotor and sociocognitive skills. HDC may also be used as a marker of maturation of sociocognitive skills during real-time social interaction. Through its standardized and objective evaluation, the HDC not only represents a valid paradigm for the study of interpersonal synchrony but also offers a promising, clinically relevant psychometric instrument for the evaluation and stratification of sociomotor dysfunctions.
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http://dx.doi.org/10.3389/fpsyt.2020.510366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725713PMC
November 2020

Fractionating autism based on neuroanatomical normative modeling.

Transl Psychiatry 2020 11 6;10(1):384. Epub 2020 Nov 6.

Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands.

Autism is a complex neurodevelopmental condition with substantial phenotypic, biological, and etiologic heterogeneity. It remains a challenge to identify biomarkers to stratify autism into replicable cognitive or biological subtypes. Here, we aim to introduce a novel methodological framework for parsing neuroanatomical subtypes within a large cohort of individuals with autism. We used cortical thickness (CT) in a large and well-characterized sample of 316 participants with autism (88 female, age mean: 17.2 ± 5.7) and 206 with neurotypical development (79 female, age mean: 17.5 ± 6.1) aged 6-31 years across six sites from the EU-AIMS multi-center Longitudinal European Autism Project. Five biologically based putative subtypes were derived using normative modeling of CT and spectral clustering. Three of these clusters showed relatively widespread decreased CT and two showed relatively increased CT. These subtypes showed morphometric differences from one another, providing a potential explanation for inconsistent case-control findings in autism, and loaded differentially and more strongly onto symptoms and polygenic risk, indicating a dilution of clinical effects across heterogeneous cohorts. Our results provide an important step towards parsing the heterogeneous neurobiology of autism.
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http://dx.doi.org/10.1038/s41398-020-01057-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648836PMC
November 2020

[The gnomAD project and the importance of having more than only one reference human genome!]

Authors:
Thomas Bourgeron

C R Biol 2020 10 9;343(2):123-125. Epub 2020 Oct 9.

Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, 75015, France.

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http://dx.doi.org/10.5802/crbiol.14DOI Listing
October 2020

Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia.

Nat Commun 2020 10 19;11(1):5272. Epub 2020 Oct 19.

Sainte Justine Hospital Research Center, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.
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http://dx.doi.org/10.1038/s41467-020-18997-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573583PMC
October 2020

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Mol Psychiatry 2021 Jul 14;26(7):3004-3017. Epub 2020 Oct 14.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience and Maastricht Brain Imaging Center (M-BIC), Maastricht University, Maastricht, The Netherlands.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10), educational attainment (0.86[0.82; 0.91]; p = 2 × 10), and intelligence (0.72[0.68; 0.76]; p = 9 × 10). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
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http://dx.doi.org/10.1038/s41380-020-00898-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505236PMC
July 2021

HyPyP: a Hyperscanning Python Pipeline for inter-brain connectivity analysis.

Soc Cogn Affect Neurosci 2021 01;16(1-2):72-83

Department of Neuroscience, Institut Pasteur, Paris, France.

The bulk of social neuroscience takes a 'stimulus-brain' approach, typically comparing brain responses to different types of social stimuli, but most of the time in the absence of direct social interaction. Over the last two decades, a growing number of researchers have adopted a 'brain-to-brain' approach, exploring similarities between brain patterns across participants as a novel way to gain insight into the social brain. This methodological shift has facilitated the introduction of naturalistic social stimuli into the study design (e.g. movies) and, crucially, has spurred the development of new tools to directly study social interaction, both in controlled experimental settings and in more ecologically valid environments. Specifically, 'hyperscanning' setups, which allow the simultaneous recording of brain activity from two or more individuals during social tasks, has gained popularity in recent years. However, currently, there is no agreed-upon approach to carry out such 'inter-brain connectivity analysis', resulting in a scattered landscape of analysis techniques. To accommodate a growing demand to standardize analysis approaches in this fast-growing research field, we have developed Hyperscanning Python Pipeline, a comprehensive and easy open-source software package that allows (social) neuroscientists to carry-out and to interpret inter-brain connectivity analyses.
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http://dx.doi.org/10.1093/scan/nsaa141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812632PMC
January 2021

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

A chimeric mouse model to study human iPSC-derived neurons: the case of a truncating SHANK3 mutation.

Sci Rep 2020 08 7;10(1):13315. Epub 2020 Aug 7.

Integrative Neurobiology of Cholinergic Systems, CNRS UMR 3571 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France.

Using human induced pluripotent stem cells (iPSC), recent studies have shown that the events underlying autism spectrum disorders (ASD) can occur during neonatal development. We previously analyzed the iPSC-derived pyramidal cortical neurons of a subset of patients with ASD carrying de novo heterozygous mutations in postsynaptic SHANK3 protein, in culture. We reported altered spinogenesis of those neurons. The transplantation of human iPSC-derived neuronal precursors into mouse brain represents a novel option for in vivo analysis of mutations affecting the human brain. In this study, we transplanted the neuronal precursor cells (NPC) into the cortex of newborn mice to analyze their integration and maturation at early stages of development and studied axonal projections of transplanted human neurons into adult mouse brain. We then co-transplanted NPC from a control individual and from a patient carrying a de novo heterozygous SHANK3 mutation. We observed a reduction in cell soma size of selective neuronal categories and in axonal projections at 30 days post-transplantation. In contrast to previous in vitro studies, we did not observe any alteration in spinogenesis at this early age. The humanized chimeric mouse models offer the means to analyze ASD-associated mutations further and provide the opportunity to visualize phenotypes in vivo.
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http://dx.doi.org/10.1038/s41598-020-70056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414912PMC
August 2020

The role of rare compound heterozygous events in autism spectrum disorder.

Transl Psychiatry 2020 06 22;10(1):204. Epub 2020 Jun 22.

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
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http://dx.doi.org/10.1038/s41398-020-00866-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308334PMC
June 2020

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles.

Sci Transl Med 2020 06;12(547)

Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.

Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children; however, the mechanism mediating hypotonia in ASD is not completely understood. Here, we used a combination of patient-derived human induced pluripotent stem cells (hiPSCs), Δ mice, and Phelan-McDermid syndrome (PMDS) muscle biopsies from patients of different ages to analyze the role of SHANK3 on motor unit development. Our results suggest that the hypotonia in SHANK3 deficiency might be caused by dysfunctions in all elements of the voluntary motor system: motoneurons, neuromuscular junctions (NMJs), and striated muscles. We found that SHANK3 localizes in Z-discs in the skeletal muscle sarcomere and co-immunoprecipitates with α-ACTININ. SHANK3 deficiency lead to shortened Z-discs and severe impairment of acetylcholine receptor clustering in hiPSC-derived myotubes and in muscle from Δ mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Δ mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD.
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http://dx.doi.org/10.1126/scitranslmed.aaz3267DOI Listing
June 2020

Insufficient Evidence for "Autism-Specific" Genes.

Am J Hum Genet 2020 05 30;106(5):587-595. Epub 2020 Apr 30.

Geisinger Autism and Developmental Medicine Institute, Danville, PA 17822, USA. Electronic address:

Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212289PMC
May 2020

Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases.

Front Mol Neurosci 2020 7;13:11. Epub 2020 Feb 7.

Department of Neuroscience, and Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.

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http://dx.doi.org/10.3389/fnmol.2020.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020611PMC
February 2020

Polygenic Architecture of Human Neuroanatomical Diversity.

Cereb Cortex 2020 04;30(4):2307-2320

Human Genetics and Cognitive Functions Unit, Institut Pasteur, UMR 3571, CNRS, Université Paris Diderot, Paris 75015, France.

We analyzed the genomic architecture of neuroanatomical diversity using magnetic resonance imaging and single nucleotide polymorphism (SNP) data from >26 000 individuals from the UK Biobank project and 5 other projects that had previously participated in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our results confirm the polygenic architecture of neuroanatomical diversity, with SNPs capturing from 40% to 54% of regional brain volume variance. Chromosomal length correlated with the amount of phenotypic variance captured, r ~ 0.64 on average, suggesting that at a global scale causal variants are homogeneously distributed across the genome. At a local scale, SNPs within genes (~51%) captured ~1.5 times more genetic variance than the rest, and SNPs with low minor allele frequency (MAF) captured less variance than the rest: the 40% of SNPs with MAF <5% captured
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http://dx.doi.org/10.1093/cercor/bhz241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175006PMC
April 2020

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Nat Commun 2019 10 29;10(1):4919. Epub 2019 Oct 29.

Department of Neurology-centre de référence des epilepsies rares, University Hospital of Strasbourg, 1 Avenue Molière, 67200, Strasbourg, France.

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
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http://dx.doi.org/10.1038/s41467-019-12763-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820781PMC
October 2019

and expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan.

Aging (Albany NY) 2019 09 12;11(17):6638-6656. Epub 2019 Sep 12.

Physiologie Moléculaire et Adaptation, CNRS UMR7221, Muséum National d'Histoire Naturelle, Département AVIV, Paris, France.

and encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development, play a role in the differentiation of certain GABAergic subclasses. Here we address the question of the functional role of Dlx5/6 in the mature central nervous system. First, we demonstrate that and are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyze mice in which and are simultaneously inactivated in all GABAergic interneurons. mice present a behavioral pattern suggesting reduction of anxiety-like behavior and obsessive-compulsive activities, and a lower interest in nest building. Twenty-month-old animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, both and mice present a 33% longer median survival. Hallmarks of biological aging such as motility, adiposity and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate healthspan and lifespan through -dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.
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http://dx.doi.org/10.18632/aging.102141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756896PMC
September 2019
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