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Fragile X syndrome (FXS) is the most common single gene ( FMR1 ) disorder affecting cognitive and behavioral function in humans. This syndrome is characterized by a cluster of abnormalities including lower IQ, attention deficits, impairments in adaptive behavior and increased incidence of autism. Here, we show that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents. Importantly, the magnitude of the PPI impairments in the fragile X children predicted the severity of their IQ, attention, adaptive behavior and autistic phenotypes. Additionally, these measures were highly correlated with each other, suggesting that a shared mechanism underlies this complex phenotypic cluster. Studies in Fmr1 -knockout mice also revealed sensorimotor gating and learning abnormalities. However, PPI and learning were enhanced rather than reduced in the mutants. Therefore, these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1–DRD5 , ADRA2A , SLC6A3 , SLC6A4 , MAOA and MAOB , and COMT . Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 ( P =0.006), ADRA2A ( P <0.02), COMT ( P <0.04), DRD3 ( P <0.05) , DRD4 ( P <0.05) , SLC6A3 ( P <0.05) and SLC6A4 ( P <0.05) genotypes were found for responders versus non-responders. Variants in DRD2 ( P <0.001) and DRD3 ( P <0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH’s efficacy and tolerability.

Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. National Institute of Mental Health.

Key Points Twin and familial studies reveal that autism spectrum disorder (ASD) traits are highly heritable. The genetic landscape of ASD is made of common and rare variants and can be different from one individual to another. Most of the ASD-risk genes are involved in chromatin remodelling, regulation of protein synthesis and degradation, or synaptic plasticity. In cellular and animal models, mutations in the ASD-risk genes lead to a distortion of typical neuronal connectivity by decreasing or increasing synapse strength or number. Compensatory mechanisms, such as genetic buffering and synaptic homeostasis, could modulate the severity of these mutations. Recent years have seen considerable interest in the genetics of autism spectrum disorder (ASD). In this Review, Thomas Bourgeron examines the genetic architecture of this disorder and how ASD-linked mutations might affect synaptic plasticity, before exploring the synaptic homeostasis hypothesis of ASD. Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability–transcription coupling, as well as histone-modifying enzymes and chromatin remodellers—most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones. Whole-exome sequencing in a large autism study identifies over 100 autosomal genes that are likely to affect risk for the disorder; these genes, which show unusual evolutionary constraint against mutations, carry de novo loss-of-function mutations in over 5% of autistic subjects and many function in synaptic, transcriptional and chromatin-remodelling pathways. Autism-linked genetic factors analysed Autism spectrum disorder (ASD) is a broad group of brain development disorders, including autism, childhood disintegrative disorder and Asperger's syndrome, characterized by impaired social interaction and communication, repetitive behaviour and restricted interests. Two groups reporting in this issue of Nature have used large-scale whole-exome sequencing to examine the contribution of inherited and germline de novo mutations to ASD risk. Silvia De Rubeis et al . analysed DNA samples from 3,871 autism cases and 9,937 ancestry-matched or parental controls and identify more than 100 autosomal genes that are likely to affect risk for the disease. De novo loss-of-function mutations were detected in more than 5% of autistic subjects. Many of the associated gene products appear to function in synaptic, transcriptional, and chromatin remodelling pathways. Ivan Iossifov et al . sequenced exomes from more than 2,500 families, each with one child with ASD. They identify 27 high-confidence gene targets and estimate that 13% of de novo missense mutations and 43% of de novo 'likely gene-disrupting' (LGD) mutations contribute to 12% and 9% of diagnoses, respectively.

The genetics of autism The autism spectrum disorders (ASDs) are a group of conditions typically characterized by repetitive behaviour, severely restricted interests and difficulties with social interactions and communication. ASDs are highly heritable, yet the underlying genetic determinants remain largely unknown. A genome-wide analysis reveals that people with ASDs carry a higher load of rare copy-number variants — segments of DNA for which the copy number differs between individual genomes — which are either inherited or arise de novo . The results implicate several novel genes as ASD candidates and point to the importance of cellular proliferation, projection and motility as well as specific signalling pathways in this disorder. The autistic spectrum disorders (ASDs) are highly heritable, yet the underlying genetic determinants remain largely unknown. Here, a genome-wide analysis of rare copy number variants (CNVs) has been carried out, revealing that ASD sufferers carry a higher load of rare, genic CNVs than do controls. Many of these CNVs are de novo and inherited. The results implicate several novel genes in ASDs, and point to the importance of cellular proliferation, projection and motility, as well as specific signalling pathways, in these disorders. The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1 . Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability 2 . Although ASDs are known to be highly heritable (∼90%) 3 , the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10 -4 ). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1 , DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Key Points SH3 and multiple ankyrin repeat domains proteins (SHANKs) are encoded by SHANK1 , SHANK2 and SHANK3 genes. The three different SHANK genes can produce multiple protein isoforms that are differentially expressed according to developmental stages, cell types and brain regions. Mutations in SHANK genes are a potential monogenic cause for autism spectrum disorder. Neurobiological studies in animal models indicate a wide array of functions for SHANK proteins, from synaptic scaffolding to regulating spine morphology and neurotransmission. Mutant mice carrying different Shank1 , Shank2 or Shank3 mutations have some distinct and shared phenotypes at the molecular and functional level. All mutants seem to have altered molecular composition of excitatory synapses and altered neurotransmission, and often display impaired social interaction and repetitive behaviour. Different mutations within the same SHANKgene may cause distinct synaptic and circuitry defects and thus may be responsible for the different clinical features that are seen in patients. Despite being a neurodevelopmental disorder, some neurobiological alterations in autism spectrum disorder may be reversible in adulthood. Adult restoration of SHANK3 levels or restoration of downstream mediators may be a useful therapeutic approach to alleviate some of the synaptic and behavioural impairments that are associated with SHANK3 mutations. Mutations in the genes encoding the SH3 and multiple ankyrin repeat domains protein (SHANK) family have been linked to autism spectrum disorder, driving a wave of recent studies that aimed to dissect their functional roles in the brain. Monteiro and Feng describe recent findings that have begun to shed light on the important roles of SHANK proteins at the synapse. Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 ( SHANK1 ), SHANK2 and SHANK3 , which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour.

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin—chromatin-remodeling network to ASD etiology.

Recent developments in the conceptualization of externalizing spectrum disorders, including attention-deficit/hyperactivity disorder, conduct disorder, antisocial personality disorder, and substance use disorders, suggest common genetic and neural substrates. Despite this, neither shared vulnerabilities nor their implications for developmental models of externalizing conduct are captured by prevailing nosologic and diagnostic systems such as the DSM-5. In the Oxford Handbook of Externalizing Spectrum Disorders, world-renowned experts on externalizing psychopathology demonstrate how shared genetic and neural vulnerabilities predispose to trait impulsivity, a highly heritable personality construct that is often shaped by adverse environments into increasingly intractable forms of externalizing conduct across development. Consistent with contemporary models of almost all forms of psychopathology, the Handbook emphasizes the importance of neurobiological vulnerability × environmental risk interactions in the expression of externalizing behavior across the life span. Furthermore, consistent with objectives of the Research Domain Criteria, which are currently being developed by the National Institute of Mental Health, chapters address causal influences across all relevant levels of analysis, including molecular genetic, behavioral genetic, hormonal, neural, family, peer, and neighborhood. The Handbook concludes with an integrative, ontogenic process model of externalizing psychopathology in which diverse equifinal and multifinal pathways to disorder are specified.