Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture, we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD

Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

25Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are 26 highly variable, and they are frequently related to other conditions besides autism. However, many different 27 variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, 28 variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this 29 advancing insight should improve clinical care, at present there is a substantial discrepancy between research 30 knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for 31 the translation of autism genetics knowledge into clinical practice. 32

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASDs and to identify subgroups of ASD cases, including those with strong acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test, and data from 6,454 families with a child with ASD, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strong acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that ASDs’ genetic influences are additive and suggest they create risk through at least partially distinct etiologic pathways.

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.

Key Points Question Do neuropsychiatric disorder genetic risk variants influence developmental trajectories of depression in youth? Findings In this population-based study including 7543 adolescents, distinct depression trajectory classes were identified. A later-adolescence–onset class (17.3% of the sample) showed a typical depression trajectory and was associated with major depressive disorder risk alleles, and an early-adolescence–onset class (9.0%) showed clinically significant symptoms at age 12 years and was associated with schizophrenia and attention-deficit hyperactivity disorder genetic risk, childhood attention-deficit hyperactivity disorder, and neurodevelopmental traits. Meaning Depression in youth is heterogeneous; findings are consistent with emerging evidence for a neurodevelopmental component to some cases of depression and that this component is more likely when onset is very early.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.