Biological Psychiatry : Autism Genotypes and Phenotypes (Mai 2015)

vendredi 5 juin 2015

Le numéro de mai 2015 de Biological Psychiatry est consacré aux phénotypes et génotypes de l’autisme.

1. Buxbaum JD. DSM-5 and Psychiatric Genetics — Round Hole, Meet Square Peg. Biol Psychiatry ;2015 ;77(9):766-768.

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2. Duyzend MH, Eichler EE. Genotype-First Analysis of the 16p11.2 Deletion Defines a New Type of “Autism”. Biol Psychiatry ;2015 ;77(9):769-771.

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3. McPartland JC, Jeste SS. Connectivity in Context : Emphasizing Neurodevelopment in Autism Spectrum Disorder. Biol Psychiatry ;2015 ;77(9):772-774.

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4. Chaste P, Klei L, Sanders SJ, Hus V, Murtha MT, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Mane SM, Martin DM, Morrow EM, Walsh CA, Sutcliffe JS, Lese Martin C, Beaudet AL, Lord C, State MW, Cook Jr EH, Devlin B. A Genome-wide Association Study of Autism Using the Simons Simplex Collection : Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity ?. Biol Psychiatry ;2015 ;77(9):775-784.

Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population ; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

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5. Hanson E, Bernier R, Porche K, Jackson FI, Goin-Kochel RP, Snyder LG, Snow AV, Wallace AS, Campe KL, Zhang Y, Chen Q, D’Angelo D, Moreno-De-Luca A, Orr PT, Boomer KB, Evans DW, Kanne S, Berry L, Miller FK, Olson J, Sherr E, Martin CL, Ledbetter DH, Spiro JE, Chung WK. The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population. Biol Psychiatry ;2015 ;77(9):785-793.

Deletion of the recurrent 600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. Methods To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent 600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. Results Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language–related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. Conclusions Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.

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6. Kitzbichler MG, Khan S, Ganesan S, Vangel MG, Herbert MR, Hämäläinen MS, Kenet T. Altered Development and Multifaceted Band-Specific Abnormalities of Resting State Networks in Autism. Biol Psychiatry ;2015 ;77(9):794-804.

Extensive evidence indicates that cortical connectivity patterns are abnormal in autism spectrum disorders (ASD), showing both overconnectivity and underconnectivity. Since, however, studies to date have focused on either spatial or spectral dimensions, but not both simultaneously, much remains unknown about the nature of these abnormalities. In particular, it remains unknown whether abnormal connectivity patterns in ASD are driven by specific frequency bands, by spatial network properties, or by some combination of these factors. Methods Magnetoencephalography recordings (15 ASD, 15 control subjects) mapped back onto cortical space were used to study resting state networks in ASD with both spatial and spectral specificity. The data were quantified using graph theoretic metrics. Results The two major factors that drove the nature of connectivity abnormalities in ASD were the mediating frequency band and whether the network included frontal nodes. These factors determined whether clustering and integration were increased or decreased in cortical resting state networks in ASD. These measures also correlated with abnormalities in the developmental trajectory of resting state networks in ASD. Lastly, these measures correlated with ASD severity in some frequency bands and spatially specific subnetworks. Conclusions Our findings suggest that network abnormalities in ASD are widespread, are more likely in subnetworks that include the frontal lobe, and can be opposite in nature depending on the frequency band. These findings thus elucidate seemingly contradictory prior findings of both overconnectivity and underconnectivity in ASD.

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7. Aceti M, Creson TK, Vaissiere T, Rojas C, Huang W-C, Wang Y-X, Petralia RS, Page DT, Miller CA, Rumbaugh G. Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly. Biol Psychiatry ;2015 ;77(9):805-815.

Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. Methods A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development. Results Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. Conclusions Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.

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8. Pinggera A, Lieb A, Benedetti B, Lampert M, Monteleone S, Liedl KR, Tuluc P, Striessnig J. CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels. Biol Psychiatry ;2015 ;77(9):816-822.

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are part of postsynaptic neuronal signaling networks. They play a key role in brain function, including fear memory and emotional and drug-taking behaviors. A whole-exome sequencing study identified a de novo mutation, p.A749G, in Cav1.3 α1-subunits (CACNA1D), the second main LTCC in the brain, as 1 of 62 high risk–conferring mutations in a cohort of patients with autism and intellectual disability. We screened all published genetic information available from whole-exome sequencing studies and identified a second de novo CACNA1D mutation, p.G407R. Both mutations are present only in the probands and not in their unaffected parents or siblings. Methods We functionally expressed both mutations in tsA-201 cells to study their functional consequences using whole-cell patch-clamp. Results The mutations p.A749G and p.G407R caused dramatic changes in channel gating by shifting ( 15 mV) the voltage dependence for steady-state activation and inactivation to more negative voltages (p.A749G) or by pronounced slowing of current inactivation during depolarizing stimuli (p.G407R). In both cases, these changes are compatible with a gain-of-function phenotype. Conclusions Our data, together with the discovery that Cav1.3 gain-of-function causes primary aldosteronism with seizures, neurologic abnormalities, and intellectual disability, suggest that Cav1.3 gain-of-function mutations confer a major part of the risk for autism in the two probands and may even cause the disease. Our findings have immediate clinical relevance because blockers of LTCCs are available for therapeutic attempts in affected individuals. Patients should also be explored for other symptoms likely resulting from Cav1.3 hyperactivity, in particular, primary aldosteronism.

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9. Machado CJ, Whitaker AM, Smith SEP, Patterson PH, Bauman MD. Maternal Immune Activation in Nonhuman Primates Alters Social Attention in Juvenile Offspring. Biol Psychiatry ;2015 ;77(9):823-832.

Sickness during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders. Rodent models have played a critical role in establishing causal relationships and identifying mechanisms of altered brain and behavior development in pups prenatally exposed to maternal immune activation (MIA). We recently developed a novel nonhuman primate model to bridge the gap between human epidemiological studies and rodent models of prenatal immune challenge. Our initial results demonstrated that rhesus monkeys given the viral mimic synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-l-lysine) during pregnancy produce offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions. Methods We utilized noninvasive infrared eye tracking to further evaluate social processing capabilities in a subset of the first trimester MIA-exposed offspring (n = 4) and control animals (n = 4) from our previous study. Results As juveniles, the MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression. Compared with control animals, MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images. Conclusions In the rhesus monkey model, exposure to MIA at the end of the first trimester results in abnormal gaze patterns to salient social information. The use of noninvasive eye tracking extends the findings from rodent MIA models to more human-like behaviors resembling those in both autism spectrum disorder and schizophrenia.

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10. McKeague IW, Brown AS, Bao Y, Hinkka-Yli-Salomäki S, Huttunen J, Sourander A. Autism with Intellectual Disability Related to Dynamics of Head Circumference Growth during Early Infancy. Biol Psychiatry ;2015 ;77(9):833-840.

It is not yet definitively known whether dynamic features of head circumference growth are associated with autism. To address this issue, we carried out a nested matched case-control study using data from national well baby clinics in Finland ; autism cases were identified from the Finnish Hospital and Outpatient Discharge Registry. Methods A nonparametric Bayesian method was used to construct growth velocity trajectories between birth and 2 years of age in autism cases and matched control subjects (n = 468 in main analyses, 1:1 matched control subjects). Estimates of odds ratios for autism risk in relation to the growth velocities were obtained using conditional logistic regression. Results Growth velocity of head circumference at 3 months of age, adjusting for gestational age at birth and maternal age, is significantly associated with autism (p = .014) ; the finding was observed in subjects with comorbid intellectual disability (ID) (p = .025) but not in those without ID (p = .15). Height growth velocity among subjects with autism and without ID is significantly associated with autism at 6 months (p = .007), and weight growth velocity at 18 months without ID (p = .02) and 24 months without ID (p = .042) and with ID (p = .037). Conclusions Acceleration in head circumference growth is associated with autism with comorbid ID at 3 months but not subsequently. This association is unrelated to acceleration in height and weight, which are not strongly associated with autism until after 6 months.

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