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Background

Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.

Methods

The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.

The etiology of autism is complex, and in most cases the underlying pathologic mechanisms are unknown. Autism is a hetereogeneous disorder, diagnosed subjectively on the basis of a large number of criteria. Recent research has investigated genetics, in utero insults and brain function as well as neurochemical and immunological factors. On the basis of family and twin studies, there appears to be a genetic basis for a wide "autistic syndrome." About a quarter of cases of autism are associated with genetic disorders such as fragile X syndrome or with infectious diseases such as congenital rubella. Genetic studies have shown an association between autism markers of brain development such as 3 markers of the c-Harvey-ros oncogene and the homeobox gene EN2. In some cases, autism is associated with insults early in gestation, including thalidomide embryopathy. Autism may arise from abnormal central nervous system functioning, since most autistic patients have indications of brain dysfunction, and about half of them have abnormal electroencephalograms. Similarly, the pattern of evoked response potentials and conduction time is altered in autistic children. There is substantial evidence from neuroimaging studies that dysfunctions in the cerebellum and possibly the temporal lobe and association cortex occur in autistic symptoms. Neurochemical studies have investigated the role of serotonin, epinephrine and norepinephrine, since levels of these neurotransmitters are altered in autism, although other hypotheses implicate overactive brain opioid systems and changes in oxytocin neurotransmission. Autoimmunity may also play a role; antibodies against myelin basic protein are often found in children with autism, who also have increased eosinophil and basophil response to IgE-mediated reactions. In summary, the prevailing view is that autism is caused by a pathophysiologic process arising from the interaction of an early environmental insult and a genetic predisposition.

Background

Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association.

Methods and Findings

We have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE) and the National Institute of Mental Health (NIMH) autism repository. We report parametric (GH, Genehunter) and allele-sharing linkage (Aspex) results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LODGH = 3.79, empirical p<0.005 and LODAspex = 2.96, p = 0.008), 15 (LODGH = 3.09, empirical p<0.005 and LODAspex = 3.62, empirical p = 0.003) and 20 (LODGH = 3.36, empirical p<0.005 and LODAspex = 3.38, empirical p = 0.006).

Conclusions

These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism.

Autism is a devastating childhood condition that has emerged as an increasing social concern just as it has increased in prevalence in recent decades. Autism and the broader category of autism spectrum disorders are among the increasingly seen examples in which there is a fetal basis for later disease or disorder. Environmental, genetic, and epigenetic factors all play a role in determining the risk of autism and some of these effects appear to be transgenerational. Identification of the most critical windows of developmental vulnerability is paramount to understanding when and under what circumstances a child is at elevated risk for autism. No single environmental factor explains the increased prevalence of autism. While a handful of environmental risk factors have been suggested based on data from human studies and animal research, it is clear that many more, and perhaps the most significant risk factors, remain to be identified. The most promising risk factors identified to date fall within the categories of drugs, environmental chemicals, infectious agents, dietary factors, and other physical/psychological stressors. However, the rate at which environmental risk factors for autism have been identified via research and safety testing has not kept pace with the emerging health threat posed by this condition. For the way forward, it seems clear that additional focused research is needed. But more importantly, successful risk reduction strategies for autism will require more extensive and relevant developmental safety testing of drugs and chemicals.

Background

Autism is a complex, heterogeneous, behaviorally-defined disorder characterized by disruptions of the nervous system and of other systems such as the pituitary-hypothalamic axis. In a previous genome wide screen, we reported linkage of autism with a 1.2 Megabase interval on chromosome 5q31. For the current study, we hypothesized that 3 of the genes in this region could be involved in the development of autism: 1) paired-like homeodomain transcription factor 1 (PITX1), which is a key regulator of hormones within the pituitary-hypothalamic axis, 2) neurogenin 1, a transcription factor involved in neurogenesis, and 3) histone family member Y (H2AFY), which is involved in X-chromosome inactivation in females and could explain the 4:1 male:female gender distortion present in autism.

Methods

A total of 276 families from the Autism Genetic Resource Exchange (AGRE) repository composed of 1086 individuals including 530 affected children were included in the study. Single nucleotide polymorphisms tagging the three candidate genes were genotyped on the initial linkage sample of 116 families. A second step of analysis was performed using tightly linked SNPs covering the PITX1 gene. Association was evaluated using the FBAT software version 1.7.3 for single SNP analysis and the HBAT command from the same package for haplotype analysis respectively.

Results

Association between SNPs and autism was only detected for PITX1. Haplotype analysis within PITX1 showed evidence for overtransmission of the A-C haplotype of markers rs11959298 – rs6596189 (p = 0.0004). Individuals homozygous or heterozygous for the A-C haplotype risk allele were 2.54 and 1.59 fold more likely to be autistic than individuals who were not carrying the allele, respectively.

Conclusion

Strong and consistent association was observed between a 2 SNPs within PITX1 and autism. Our data suggest that PITX1, a key regulator of hormones within the pituitary-hypothalamic axis, may be implicated in the etiology of autism.

Lay Abstract

Autism is a complex developmental disability characterized by abnormalities in spoken language, socialization and repetitive behaviors. In recent years, an increase in the number of autism cases worldwide has been reported. Researchers have found evidence that autism is caused by multiple genetic factors, and a number of potential risk genes have been identified. Earlier we have found an increased frequency in subject with autism of a form of the enzyme glyoxalase I (Glo1) that has glutamic acid at position 111. By using lymphoblastoid and neuronal cells in culture, we now present evidence that this form of Glo1 is reduced in function, and consequently accumulates a toxic metabolite called methylglyoxal (MG). MG can form conjugates with cellular proteins, thereby compromising their function. We propose that an increase in conjugated proteins causes over-expression of receptors that bind these altered proteins, which in turn can initiate cascades of potentially harmful events. These studies suggest that in a subset of individuals with autism, the occurrence of the Glo1 polymorphism may precipitate changes in cellular structure and function that support risk for autism.

Scientific Abstract

Autism is a pervasive, heterogeneous, neurodevelopmental disability characterized by impairments in verbal communications, reciprocal social interactions, and restricted repetitive stereotyped behaviors. Evidence suggests the involvement of multiple genetic factors in the etiology of autism, and extensive genome-wide association studies have revealed several candidate genes that bear single nucleotide polymorphisms (SNPs) in non-coding and coding regions. We have shown that a non-conservative, non-synonymous SNP in the glyoxalase I gene, GLOI, may be an autism susceptibility factor. The GLOI rs2736654 SNP is a C→A change that causes an Ala111Glu change in the Glo1 enzyme. To identify the significance of the SNP, we have conducted functional assays for Glo1. We now present evidence that the presence of the A-allele at rs2736654 results in reduced enzyme activity. Glo1 activity is decreased in lymphoblastoid cells that are homozygous for the A allele. The Glu-isoform of Glo1 in these cells is hyperphosphorylated. Direct HPLC measurements of the glyoxalase I substrate, methylglyoxal (MG), show an increase in MG in these cells. Western blot analysis revealed elevated levels of the receptor for advanced glycation end products (RAGEs). We also show that MG is toxic to the developing neuronal cells. We suggest that accumulation of MG results in the formation of AGEs, which induce expression of the RAGE that during crucial neuronal development may be a factor in the pathology of autism.

Background

The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system.

Methods

SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism.

Results

We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 × 10-6 and 1.9 × 10-5, respectively).

Conclusions

Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism.

Autism is a complex genetic disorder with multiple etiologies whose molecular genetic basis is not fully understood. Although a number of rare mutations and dosage abnormalities are specific to autism, these explain no more than 10% of all cases. The high heritability of autism and low recurrence risk suggests multifactorial inheritance from numerous loci but other factors also intervene to modulate risk. In this study, we examine the effect of birth rank on disease risk which is not expected for purely hereditary genetic models.

We analyzed the data from three publicly available autism family collections in the USA for potential birth order effects and studied the statistical properties of three tests to show that adequate power to detect these effects exist. We detect statistically significant, yet varying, patterns of birth order effects across these collections. In multiplex families, we identify V-shaped effects where middle births are at high risk; in simplex families, we demonstrate linear effects where risk increases with each additional birth. Moreover, the birth order effect is gender-dependent in the simplex collection. It is currently unknown whether these patterns arise from ascertainment biases or biological factors. Nevertheless, further investigation of parental age-dependent risks yields patterns similar to those observed and could potentially explain part of the increased risk. A search for genes considering these patterns is likely to increase statistical power and uncover novel molecular etiologies.

Biomes are areas of vegetation that are characterized by the same life-form. Traditional definitions of biomes have also included either geographical or climatic descriptors. This approach describes a wide range of biomes that can be correlated with characteristic climatic conditions, or climatic envelopes. The application of remote sensing technology to the frequent observation of biomes has led to a move away from the often subjective definition of biomes to one that is objective. Carefully characterized observations of life-form, by satellite, have been used to reconsider biome classification and their climatic envelopes. Five major tree biomes can be recognized by satellites based on leaf longevity and morphology: needleleaf evergreen, broadleaf evergreen, needleleaf deciduous, broadleaf cold deciduous and broadleaf drought deciduous. Observations indicate that broadleaf drought deciduous vegetation grades substantially into broadleaf evergreen vegetation. The needleleaf deciduous biome occurs in the world's coldest climates, where summer drought and therefore a drought deciduous biome are absent. Traditional biome definitions are quite static, implying no change in their life-form composition with time, within their particular climatic envelopes. However, this is not the case where there has been global ingress of grasslands and croplands into forested vegetation. The global spread of grasses, a new super-biome, was probably initiated 30-45 Myr ago by an increase in global aridity, and was driven by the natural spread of the disturbances of fire and animal grazing. These disturbances have been further extended over the Holocene era by human activities that have increased the land areas available for domestic animal grazing and for growing crops. The current situation is that grasses now occur in most, if not all biomes, and in many areas they dominate and define the biome. Croplands are also increasing, defining a new and relatively recent component to the grassland super-biome. In the case of both grassland and croplands, various forms of disturbance, particularly frequent disturbance, lead to continued range extensions of the biomes.

There is an urgent need to develop better therapeutics for autoimmune and autoinflammatory diseases, of which musculoskeletal disorders such as rheumatoid arthritis are particularly prevalent and debilitating. Helminth parasites are accomplished masters at modifying their hosts' immune activity, and so attention has focused on rodent-helminth model systems to uncover the workings of the mammalian immune response to metazoan parasites, with the hope of revealing molecules and/or mechanisms that can be translated into better treatments for human autoimmune and idiopathic disorders. Substantial proof-of-principal data supporting the concept that infection with helminth parasites can reduce the severity of concomitant disease has been amassed from models of mucosal inflammation. Indeed, infection with helminth parasites has been tried as a therapy in inflammatory bowel disease, and there are case reports relating to other conditions (e.g., autism); however, the impact of infection with parasitic helminths on musculoskeletal diseases has not been extensively studied. Here, we present the view that such a strategy should be applied to the amelioration of joint inflammation and review the literature that supports this contention.

This study examined the frequency of personality, language, and social-behavioral characteristics believed to comprise the broad autism phenotype (BAP), across families differing in genetic liability to autism. We hypothesized that within this unique sample comprised of multiple-incidence autism families (MIAF), single-incidence autism families (SIAF), and control Down syndrome families (DWNS), a graded expression would be observed for the principal characteristics conferring genetic susceptibility to autism, in which such features would express most profoundly among parents from MIAFs, less strongly among SIAFs, and least of all among comparison parents from DWNS families, who should display population base rates. Analyses detected linear expression of traits in line with hypotheses, and further suggested differential intrafamilial expression across family types. In the vast majority of MIAFs both parents displayed BAP characteristics, whereas within SIAFs, it was equally likely that one, both, or neither parent show BAP features. The significance of these findings is discussed in relation to etiologic mechanisms in autism and relevance to molecular genetic studies.

Background

Executive dysfunctions have been studied as a potential endophenotype associated with the genetic basis of autism. Given that recent findings from clinical and molecular genetic studies suggest that autism and obsessive-compulsive disorder (OCD) could share a common pattern of heritability, we assessed executive functions as a possible common cognitive endophenotype in unaffected family members of individuals with either autism or OCD.

Methods

Five tests assessing executive functions (Tower of London, verbal fluency, design fluency, trail making and association fluency) were proposed to 58 unaffected first-degree relatives (parents and siblings) of probands with autism and 64 unaffected first-degree relatives of OCD patients. Results were compared with those of 47 healthy controls matched for age, sex, and level of education.

Results

In the Tower of London test, both groups of unaffected relatives showed significantly lower scores and longer response times compared with controls. No differences were observed between autism and OCD relatives and healthy controls in the four other tasks (verbal fluency, design fluency, trail making test and association fluency).

Conclusions

Our findings show the existence of executive dysfunction in the unaffected first-degree relatives of probands with OCD, similar to those observed in the relatives of patients with autism. These results support and extend previous cognitive studies on probands indicating executive dysfunctions in autism and OCD. Planning and working memory processes could thus represent a common cognitive endophenotype in autism and OCD that could help in the identification of genes conferring vulnerability to these disorders.

Summary

Although autism is one of the most heritable neuropsychiatric disorders, its underlying genetic architecture has largely eluded description. To comprehensively examine the hypothesis that common variation is important in autism, we performed a genome-wide association study (GWAS) using a discovery dataset of 438 autistic Caucasian families and the Illumina Human 1M beadchip. 96 single nucleotide polymorphisms (SNPs) demonstrated strong association with autism risk (p-value < 0.0001). The validation of the top 96 SNPs was performed using an independent dataset of 487 Caucasian autism families genotyped on the 550K Illumina BeadChip. A novel region on chromosome 5p14.1 showed significance in both the discovery and validation datasets. Joint analysis of all SNPs in this region identified 8 SNPs having improved p-values (3.24E-04 to 3.40E-06) than in either dataset alone. Our findings demonstrate that in addition to multiple rare variations, part of the complex genetic architecture of autism involves common variation.

The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.

Autism spectrum disorders (ASD’S) are highly heritable. Consequently, gene discovery promises to help illuminate the pathophysiology of these syndromes, yielding important opportunities for the development of novel treatments and a more nuanced understanding of the natural history of these disorders. Although the underlying genetic architecture of ASD’s is not yet known, the literature demonstrates that it is not, writ large, a monogenic disorder with Mendelian inheritance, but rather a group of complex genetic syndromes with risk deriving from genetic variations in multiple genes. The widely accepted “Common Disease-Common Variant” hypothesis predicts that the risk alleles in ASD’s and other complex disorders will be common in the general population. However, recent evidence from gene discovery efforts in a wide range of diseases raises important questions regarding the overall applicability of the theory and the extent of its usefulness in explaining individual genetic liability. In contrast, considerable evidence points to the importance of rare alleles both with regard to their value in providing a foothold into the molecular mechanisms of ASD and their overall contribution to the population-wide risk. This chapter reviews the origins of the common versus rare variant debate, highlights recent findings in the field, and addresses the clinical implications of both common and rare variant discoveries.

The presence of autism-related traits has been well documented in undiagnosed family members of individuals with autism spectrum disorder (ASD). The most common finding is mild impairments in social and communication skills that are similar to those shown by individuals with autism, but exhibited to a lesser degree. Termed the broader autism phenotype (BAP), these traits suggest a genetic liability for autism-related traits in families. Genetic influence in autism is strong, with identical twins showing high concordance for the diagnosis and related traits and approximately 20% of all ASD cases having an identified genetic mechanism. This paper highlights the studies conducted to date regarding the BAP and considers the implications of these findings for the etiology and treatment of ASD.

Background

The search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity.

Methods

In this study, using 976 multiplex families from the Autism Genome Project consortium, we performed genome-wide linkage analyses on two quantitative subphenotypes, the total scores of the reciprocal social interaction domain and the restricted, repetitive, and stereotyped patterns of behavior domain from the Autism Diagnostic Interview-Revised. We also selected subsets of ASD families based on four binary subphenotypes, delayed onset of first words, delayed onset of first phrases, verbal status, and IQ ≥ 70.

Results

When the ASD families with IQ ≥ 70 were used, a logarithm of odds (LOD) score of 4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3 using the ASD families with delayed onset of first phrases. No significant evidence for linkage was obtained for the two quantitative traits.

Conclusions

This study demonstrates that selection of informative subphenotypes to define a homogeneous set of ASD families could be very important in detecting the susceptibility loci in autism.

Aim

Deficiency of Alpha-1-antitrypsin (AAT) can be a genetic condition that increases the risk of developing liver, lung and possibly gastrointestinal disease. Since many autistic children also have gastrointestinal disorders, this study was designed to measure serum concentration of AAT and establish AAT genotypes in autistic children, age and gender matched non-autistic siblings, parents and controls.

Subjects and Methods

We used an indirect ELISA with monoclonal IgG to AAT to measure AAT serum concentrations in 71 members from 16 families of individuals with autism and 18 controls (no family history of autism). We used a duplex polymerase chain reaction to detect M, S and Z alleles for alpha-1 antitrypsin expression in 52 members of 12 of the above families.

Results

A significantly high number of autistic family members had lower than normal serum levels of AAT when compared to controls. Autistic children with regressive onset had significantly lower levels of AAT compared to controls, and a significant number of autistic children with low serum AAT also had hyperbilirubinemia, gastrointestinal disease and respiratory problems. We also found that a significantly high number of these individuals had the PiMZ genotype and correspondingly low levels of serum alpha-1 antitrypsin.

Discussion

Knowing that low levels of alpha-1 antitrypsin may be inherited, and that low levels of AAT may be associated with GI disease in autistic children, genotyping autistic children may help identify individuals susceptible to developing digestive problems.

Scaling relations among plant traits are both cause and consequence of processes at organ-to-ecosystem scales. The relationship between leaf nitrogen and phosphorus is of particular interest, as both elements are essential for plant metabolism; their limited availabilities often constrain plant growth, and general relations between the two have been documented. Herein, we use a comprehensive dataset of more than 9300 observations of approximately 2500 species from 70 countries to examine the scaling of leaf nitrogen to phosphorus within and across taxonomical groups and biomes. Power law exponents derived from log–log scaling relations were near 2/3 for all observations pooled, for angiosperms and gymnosperms globally, and for angiosperms grouped by biomes, major functional groups, orders or families. The uniform 2/3 scaling of leaf nitrogen to leaf phosphorus exists along a parallel continuum of rising nitrogen, phosphorus, specific leaf area, photosynthesis and growth, as predicted by stoichiometric theory which posits that plants with high growth rates require both high allocation of phosphorus-rich RNA and a high metabolic rate to support the energy demands of macromolecular synthesis. The generality of this finding supports the view that this stoichiometric scaling relationship and the mechanisms that underpin it are foundational components of the living world. Additionally, although abundant variance exists within broad constraints, these results also support the idea that surprisingly simple rules regulate leaf form and function in terrestrial ecosystems.

Heavy metals including mercury, lead, and cadmium are present throughout the ecosystem and are detectable in small amounts in the Great Lakes water and fish. The main route of exposure of humans to these metals is via the ingestion of contaminated food, especially fish. Extensive experimental investigations indicated that heavy metals alter a number of parameters of the host's immune system and lead to increased susceptibility to infections, autoimmune diseases, and allergic manifestations. The existing limited epidemiologic data and data derived from in vitro systems in which human peripheral blood leukocytes were used suggested that the human immune system may also be at increased risk following exposure to these metals. The magnitude of the risk that the presence of such metals in the Great Lakes may pose to the human immune system, and consequently to their health, is not known. In this review, the available data with respect to potential adverse effects of heavy metals on the immune system of humans and experimental animals are discussed, and additional data requirements are suggested.

Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1 deficient mice in autism and mental retardation-relevant behavioral tasks. NL1 KO mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive stereotyped grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at cortico-striatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial co-agonist D-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and neuroligin-1 in particular, in autism, and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.

More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10–20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain.

The role of the immune system in neuropsychiatric diseases, including autism spectrum disorder (ASD), has long been hypothesized. This hypothesis has mainly been supported by family cohort studies and the immunological abnormalities found in ASD patients, but had limited findings in genetic association testing. Two cross-disorder genetic association tests were performed on the genome-wide data sets of ASD and six autoimmune disorders. In the polygenic score test, we examined whether ASD risk alleles with low effect sizes work collectively in specific autoimmune disorders and show significant association statistics. In the genetic variation score test, we tested whether allele-specific associations between ASD and autoimmune disorders can be found using nominally significant single-nucleotide polymorphisms. In both tests, we found that ASD is probabilistically linked to ankylosing spondylitis (AS) and multiple sclerosis (MS). Association coefficients showed that ASD and AS were positively associated, meaning that autism susceptibility alleles may have a similar collective effect in AS. The association coefficients were negative between ASD and MS. Significant associations between ASD and two autoimmune disorders were identified. This genetic association supports the idea that specific immunological abnormalities may underlie the etiology of autism, at least in a number of cases.

Symposium 5 focused on research approaches that are aimed at understanding common patterns of immunological and neurological dysfunction contributing to neurodevelopmental disorders such as autism and ADHD. The session focused on genetic, epigenetic, and environmental factors that might act in concert to influence autism risk, severity and co-morbidities, and immunological and neurobiological targets as etiologic contributors. The immune system of children at risk of autism may be therefore especially susceptible to psychological stressors, exposure to chemical triggers, and infectious agents. Identifying early biomarkers of risk provides tangible approaches toward designing studies in animals and humans that yield a better understanding of environmental risk factors, and can help identify rational intervention strategies to mitigate these risks.

Autism is characterized as one of the Pervasive Developmental Disorders (PDDs), a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-HT) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 SNPs in 10 serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p=0.0002; p=0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on Chromosome 11 (~113 Mb). To test specifically for multilocus effects, Multifactor Dimensionality Reduction (MDR) was employed, and a significant 2-way interaction (p-value = 0.01) was found between rs10830962, near MTNR1B (Chromosome11; 92,338,075 bp) and rs1007631, near SLC7A5 (Chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk.