Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors.

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1 -4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5 -9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11 , 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10 −3 ). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10 −3 ). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10 −6 ). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates in the United States are 0.1-0.2% for autism and 0.6% for ASDs 1,2 .Linkage and candidate gene association studies have implicated several chromosomal regions in autism 3,4 . However, positive findings in one study often fail to replicate in other studies, and a consistent picture of susceptibility loci in autism is still lacking. Some telling clues about ASD genetics arose from recent studies on CNVs 5 , including the association of de novo CNVs with ASDs 6 . Although de novo CNVs that disrupt specific genes may contribute to the pathogenesis of ASDs, heritable CNVs are much more common but have been less studied as risk factors of ASDs. A family-based genome-wide linkage and CNV analysis by the Autism Genome Project Consortium using Affymetrix 10K single nucleotide polymorphism (SNP) arrays implicated chromosome 11p12-13 and neurexin 1 (NRXN1) as candidate loci 7 . A study using the Affymetrix 500K SNP array in a Canadian population reported 277 rare CNVs that were only observed in ASD patients but not in 1,652 healthy controls or in the Database of Genomic Variants 8 . Furthermore, 16p11.2 deletions and Glessner et al.Page 2 Nature. Author manuscript; available in PMC 2010 August 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscri...

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

We report the prevalence rates for dementia and Alzheimer's disease (AD) obtained from a probability sample survey of 5,055 noninstitutionalized older persons in Shanghai, China. A two-stage procedure was used for case finding and case identification. A Chinese version of the Mini-Mental State Examination was used to determine cases of possible dementia. Three different cutoff points on this mental status test were used depending on the respondent's level of education. Clinical evaluations, based on functional assessments and psychiatric interview, medical and neurological examinations, three standardized mental status tests, and a selected group of psychometric tests, were made in the second stage of the study to ascertain the clinical diagnosis of dementia and AD utilizing the Diagnostic and Statistical Manual for Mental Disorders, edition 3 and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively. The prevalence rate of dementia in persons 65 years and older was 4.6%. Clinically diagnosed AD accounted for 65% of the subjects with dementia. These findings indicate that the prevalence of dementia in Shanghai is very much higher than figures published earlier for China and Japan, and at the lower part of the range of values reported for community residents in the United States and other Western countries, but less than half of that reported in the recently published survey of the elderly in East Boston. Increasing age, gender (female), and low education are each highly significant and independent risk factors for dementia. One hypothesis to explain the increased prevalence in elderly women who had received no formal education invokes the possibility of an effect of early deprivation, perhaps lowering brain "reserve," allowing the symptoms of dementia to appear at an earlier date during disease progression.

Background22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.MethodsA serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.ResultsThirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.ConclusionsThis study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

SummaryAlthough autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants.