SUMMARY Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

BackgroundOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).MethodsWe conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).ResultsWe observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10−6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a ‘neurodevelopmental hub’ on chromosome 8p11.23.ConclusionsThis study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4. Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0137-9) contains supplementary material, which is available to authorized users.

Daily living skills (DLS), such as personal hygiene, meal preparation, and money management, are important to independent living. Research suggests that many individuals with autism spectrum disorder exhibit impairments in daily living skills relative to their cognitive skills. This study examined predictors of daily living skills attainment and trajectories of daily living skills in a longitudinal sample referred for possible autism spectrum disorder and followed from 2 to 21 years of age. Consistent with previous studies, participants with autism spectrum disorder and nonspectrum diagnoses showed continual development of daily living skills throughout childhood and adolescence. Early childhood nonverbal mental age was the strongest predictor of daily living skills attainment for both diagnostic groups. Group-based modeling suggested two distinct trajectories of daily living skills development for participants with autism spectrum disorder. Skill levels for both groups of young adults with autism spectrum disorder remained considerably below age level expectations. Whereas the “High-DLS” group gained approximately 12 years in daily living skills from T2 to T21, the “Low-DLS” group’s daily living skills improved 3–4 years over the 16- to 19-year study period. Nonverbal mental age, receptive language, and social-communication impairment at 2 years predicted High- versus Low-DLS group membership. Receiving greater than 20 h of parent-implemented intervention before age 3 was also associated with daily living skills trajectory. Results suggest that daily living skills should be a focus of treatment plans for individuals with autism spectrum disorder, particularly adolescents transitioning to young adulthood.

Standardized calibrated severity scores (CSS) have been created for Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) Modules 1–4 as a metric of the relative severity of autism-specific behaviors. Total and domain CSS were created for the Toddler Module to facilitate comparison to other modules. Analyses included 388 children with ASD age 12 to 30 months and were replicated on 435 repeated assessments from 127 children with ASD. Compared to raw scores, associations between total and domain CSS and participant characteristics were reduced in the original sample. Verbal IQ effects on Social Affect-CSS were not reduced in the replication sample. Toddler Module CSS increases comparability of ADOS-2 scores across modules and allows studies of symptom trajectories to extend to earlier ages.