Autism and environmental genomics

Autism spectrum disorders (ASD) are defined by behavior and diagnosed by clinical history and observation but have no biomarkers and are presumably, etiologically and biologically heterogeneous. Given brain abnormalities and high monozygotic concordance, ASDs have been framed as neurobiologically based and highly genetic, which has shaped the research agenda and in particular criteria for choosing candidate ASD genes. Genetic studies to date have not uncovered genes of strong effect, but a move toward "genetic complexity" at the neurobiological level may not suffice, as evidence of systemic abnormalities (e.g. gastrointestinal and immune), increasing rates and less than 100% monozygotic concordance support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors. We review this evidence and also use a bioinformatic approach to explore the possibility that "environmentally responsive genes" not specifically associated with the nervous system, but potentially associated with systemic changes in autism, have not hitherto received sufficient attention in autism genetics investigations. We overlapped genes from NIEHS Environmental Genome Project, the Comparative Toxicogenomics Database, and the SeattleSNPs database of genes relevant to the human immune and inflammatory response with linkage regions identified in published autism genome scans. We identified 135 genes in overlap regions, of which 56 had never previously been studied in relation to autism and 47 had functional SNPs (in coding regions). Both our review and the bioinformatics exercise support the expansion of criteria for evaluating the relevance of genes to autism risk to include genes related to systemic impact and environmental responsiveness. This review also suggests the utility of environmental genomic resources in highlighting the potential relevance of particular genes within linkage regions. Environmental responsiveness and systems impacts consistent with system-wide findings in autism are thus supported as important considerations in identifying the numerous and complex modes of gene-environment interaction in autism.     

Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression

Autism is a pervasive developmental disorder with a strong genetic component. While candidate regions of the genome have been identified, location of genes conferring susceptibility to autism has been hindered by the heterogeneity within this clinically defined disorder, and the likely contribution of many genes of weak effect. Subsetting samples on the basis of distinct, nondiagnostic clinical features has been recommended to decrease sample heterogeneity. In this study, linkage analysis was performed on a subset of families in the database of the Autism Genetic Resource Exchange (AGRE). This set of autism-affected relative pairs (n=34) was also concordant for a history of developmental regression as measured by the Autism Diagnostic Interview-Revised (ADI-R). In this sample, a maximum multipoint LOD score of 3.4 under the dominant mode of inheritance and an NPL score of 3.0 (P=1.3 x 10(-3)) were observed on chromosome 21 near D21S1437. On chromosome 7 near D7S483 a LOD score of 2.0 under the dominant mode of inheritance and an NPL score of 3.7 (P=7.9 x 10(-5)) were observed. Genetic elements in these regions of 21q and 7q are likely to confer susceptibility to autism or modify the disease presentation in a subgroup of children characterized by a history of developmental regression.     

A novel hereditary spastic paraplegia with dystonia linked to chromosome 2q24‐2q31

Spastic paraplegias (HSPs) and dystonias (DYTs) typically localize to different neuroanatomic systems. We report clinical and genetic data from large Ohio kindred with autosomal dominant (AD) HSP and DYT. Single and multipoint linkage using microsatellite and single nucleotide polymorphism array genotyping were performed on a large, multigenerational family with a novel, AD, highly penetrant neurological disease causing spasticity and DYT. Age of onset of spasticity and weakness is from the first year to the sixth decade, and age of onset of DYT from the first to third decade. There is no ataxia or apparent cognitive involvement. Neuroimaging and peripheral neurophysiology are normal. Generalized DYT improved markedly with deep brain stimulation in 1 child. The disease locus was mapped to a region on chromosome 2q 24–31, flanked by markers rs1424937–rs1559510, proximal to SPG13, in a region where there are no known HSP or DYT genes. A secondary analysis for candidate genes segregating with the DYT phenotype revealed two candidate regions with parametric lod scores above 2.0. On the basis of clinical presentation and linkage results, we conclude that this disease is a novel neurological disorder. Identifying the causative gene may elucidate an important pathway for pyramidal and extrapyramidal disorders. © 2008 Movement Disorder Society     

The molecular genetics of the 22q11-associated schizophrenia

Schizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A number of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 Mb critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown.     

Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.     

Current developments in the genetics of autism: from phenome to genome

Despite compelling evidence from twin and family studies indicating a strong genetic involvement in the etiology of autism, the unequivocal detection of autism susceptibility genes remains an elusive goal. The purpose of this review is to evaluate the current state of autism genetics research, with attention focused on new techniques and analytic approaches. We first present a brief overview of evidence for the genetic basis of autism, followed by an appraisal of linkage and candidate gene study findings and consideration of new analytic approaches to the study of complex psychiatric conditions, namely, genome-wide association studies, assessment of structural variation within the genome, and the incorporation of endophenotypes in genetic analysis.     

Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism

Autism is a developmental disorder characterized by impairments in social interaction and communication associated with repetitive patterns of interest or behavior. Autism is highly influenced by genetic factors. Genome-wide linkage and candidate gene association approaches have been used to try and identify autism genes. A few loci have repeatedly been reported linked to autism. Several groups reported evidence for linkage to a region on chromosome 16p. We have applied a direct physical identity-by-descent (IBD) mapping approach to perform a high-density (0.85 megabases) genome-wide linkage scan in 116 families from the AGRE collection. Our results confirm linkage to a region on chromosome 16p with autism. High-resolution single-nucleotide polymorphism (SNP) genotyping and analysis of this region show that haplotypes in the protein kinase c-beta gene are strongly associated with autism. An independent replication of the association in a second set of 167 trio families with autism confirmed our initial findings. Overall, our data provide evidence that the PRKCB1 gene on chromosome 16p may be involved in the etiology of autism.     

A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence

Autism is a neurodevelopmental disorder with high heritability and a likely complex genetic architecture. Much genetic evidence has accumulated in the last 20 years but no gene has been unequivocally identified as containing risk variants for autism. In this article we review the past and present literature on neuro-pathological, genetic linkage, genetic association, and gene expression studies in this disorder. We sought convergent evidence to support particular genes or chromosomal regions that might be likely to contain risk DNA variants. The convergent evidence from these studies supports the current hypotheses that there are multiple genetic loci predisposing to autism, and that genes involved in neurodevelopment are especially important for future genetic studies. Convergent evidence suggests the chromosome regions 7q21.2-q36.2, 16p12.1-p13.3, 6q14.3-q23.2, 2q24.1-q33.1, 17q11.1-q21.2, 1q21-q44 and 3q21.3-q29, are likely to contain risk genes for autism. Taken together with results from neuro-pathological studies, genes involved in brain development located at the above regions should be prioritized for future genetic research.     

Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in Finnish multiplex families

The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population.     

Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental condition that results in behavioral, social and communication impairments. ASD has a substantial genetic component, with 88–95% trait concordance among monozygotic twins. Efforts to elucidate the causes of ASD have uncovered hundreds of susceptibility loci and candidate genes. However, owing to its polygenic nature and clinical heterogeneity, only a few of these markers represent clear targets for further analyses. In the present study, we used the linkage structure associated with published genetic markers of ASD to simultaneously improve candidate gene detection while providing a means of prioritizing markers of common genetic variation in ASD. We first mined the literature for linkage and association studies of single-nucleotide polymorphisms, copy-number variations and multi-allelic markers in Autism Genetic Resource Exchange (AGRE) families. From markers that reached genome-wide significance, we calculated male-specific genetic distances, in light of the observed strong male bias in ASD. Four of 67 autism-implicated regions, 3p26.1, 3p26.3, 3q25-27 and 5p15, were enriched with differentially expressed genes in blood and brain from individuals with ASD. Of 30 genes differentially expressed across multiple expression data sets, 21 were within 10 cM of an autism-implicated locus. Among them, CNTN4, CADPS2, SUMF1, SLC9A9, NTRK3 have been previously implicated in autism, whereas others have been implicated in neurological disorders comorbid with ASD. This work leverages the rich multimodal genomic information collected on AGRE families to present an efficient integrative strategy for prioritizing autism candidates and improving our understanding of the relationships among the vast collection of past genetic studies.     

Autism: in search of susceptibility genes

Autism is a neurodevelopmental disorder of unknown etiology. There is convincing data for the involvement of genetic factors in the development of autism, and the absence of any consistent evidence for an environmental, neuroanatomical, or biochemical cause has led to an increasing number of genetic studies to determine the basis of this complex disorder. The results of recent genetic linkage and candidate gene studies are reviewed in relation to the challenge of clinical and genetic heterogeneity, and prospects for the future of genetic research in autism are considered.     

Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism

The identification of the candidate genes for autism through linkage and association studies has proven to be a difficult enterprise. An alternative approach is the analysis of cytogenetic abnormalities associated with autism. We present a review of all studies to date that relate patients with cytogenetic abnormalities to the autism phenotype. A literature survey of the Medline and Pubmed databases was performed, using multiple keyword searches. Additional searches through cited references and abstracts from the major genetic conferences from 2000 onwards completed the search. The quality of the phenotype (i.e. of the autism spectrum diagnosis) was rated for each included case. Available specific probe and marker information was used to define optimally the boundaries of the cytogenetic abnormalities. In case of recurrent deletions or duplications on chromosome 15 and 22, the positions of the low copy repeats that are thought to mediate these rearrangements were used to define the most likely boundaries of the implicated 'Cytogenetic Regions Of Interest' (CROIs). If no molecular data were available, the sequence position of the relevant chromosome bands was used to obtain the approximate molecular boundaries of the CROI. The findings of the current review indicate: (1) several regions of overlap between CROIs and known loci of significant linkage and/or association findings, and (2) additional regions of overlap among multiple CROIs at the same locus. Whereas the first finding confirms previous linkage/association findings, the latter may represent novel, not previously identified regions containing genes that contribute to autism. This analysis not only has confirmed the presence of several known autism risk regions but has also revealed additional previously unidentified loci, including 2q37, 5p15, 11q25, 16q22.3, 17p11.2, 18q21.1, 18q23, 22q11.2, 22q13.3 and Xp22.2-p22.3.     

Bipolar affective disorder in a male with a deletion of Y chromosome -- a case report

We report on a 25-year-old male with bipolar disorder, dysmorphic features and a deletion of the long arm of Y chromosome. A potential association between sex chromosome abnormalities and a susceptibility to major psychiatric disorders has been documented. However there have been very few reports on the coincidence of Y chromosome aberrations with bipolar disorder. Cytogenetic studies have contributed to the identification of several disease genes. Karyotyping of patients with bipolar disorder in order to identify candidate regions for linkage studies has been recommended.     

Genetic advances in autism hinge on the method of measuring symptoms

Advances in genotyping and related technologies and the study of families with two or more autistic siblings have allowed the reporting of various genetic linkage and candidate gene association studies for autism. Despite this significant research effort, there still is no general agreement on the role of particular genes that predispose to the risk of autism. One source of general debate is whether core symptoms studied in research on the heredity of autism include single or multiple independent genetic domains. In this review, it is argued that failure to control for co-existing dimensions of psychopathology and lack of assessment of parents may lead to misinterpretation of genetic findings from pedigrees involving multiple affected family members.     

A Case of Partial Trisomy of Chromosome 8p Associated with Autism

We report on a case of a 6-year-old female with partial trisomy 8p(21–23) associated with autism, mild dysmorphic features, and moderate learning disability. Although mental retardation is a common finding in patients with mosaic trisomy 8 or partial trisomy of various regions of chromosome 8, only two cases associated with autism have been reported so far. Also, in our case clinical manifestations were mild compared to other patients with duplication of the same region of chromosome 8. Although there has been no strong evidence for linkage on chromosome 8 in any of the genome-wide linkage studies so far, the possibility that this segment includes genes involved in the etiology of autism should be further explored.     

Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12

Previous genome-wide linkage studies applied the affected sib-pair design; one investigated extended pedigrees of a genetic isolate. Here, results of a genome-wide high-density linkage scan of attention-deficit/hyperactivity disorder (ADHD) using an array-based genotyping of approximately 50 K single nucleotide polymorphism (SNPs) markers are presented. We investigated eight extended pedigrees of German origin that were non-related, not part of a genetic isolate and ascertained on the basis of clinical referral. Two parametric analyses maximizing LOD scores (MOD) and a non-parametric analysis for both a broad and a narrow phenotype approach were conducted. Novel linkage loci across all families were detected at 2q35, 5q13.1, 6q22-23 and 14q12, within individual families at 18q11.2-12.3. Further linkage regions at 7q21.11, 9q22 and 16q24.1 in all families, and at 1q25.1, 1q25.3, 9q31.1-33.1, 9q33, 12p13.33, 15q11.2-13.3 and 16p12.3-12.2 in individual families replicate previous findings. High-resolution linkage mapping points to several novel candidate genes characterized by dense expression in the brain and potential impact on disorder-relevant synaptic transmission. Our study provides further evidence for common gene effects throughout different populations despite the complex multifactorial etiology of ADHD.     

A theoretical molecular network for dyslexia: integrating available genetic findings

Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network.     

Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene

The results from several genome scans indicate that chromosome 2q21-q33 is likely to contain an autism susceptibility locus. We studied the potential contribution of nine positional and functional candidate genes: TBR-1; GAD1; DLX1; DLX2; cAMP-GEFII; CHN1; ATF2; HOXD1 and NEUROD1. Screening these genes for DNA variants and association analysis using intragenic single nucleotide polymorphisms did not provide evidence for a major role in the aetiology of autism. Four rare nonsynonymous variants were identified, however, in the cAMP-GEFII gene. These variants were present in five families, where they segregate with the autistic phenotype, and were not observed in control individuals. The significance of these variants is unclear, as their low frequency in IMGSAC families does not account for the relatively strong linkage signal at the 2q locus. Further studies are needed to clarify the contribution of cAMP-GEFII gene variants to autism susceptibility.     

Heterogeneity and the genetics of autism

The objective of this review is to summarize recent data on the genetics of autism, highlight the evidence for genetic heterogeneity and extend the implications of these findings for the identification of susceptibility genes in this disorder. Family studies have shown that autism runs in families and twin studies indicate that the basis of that familial aggregation is genetic. As a result the prospects for the identification of susceptibility genes using either linkage or association studies are quite good. However, recent evidence is accumulating suggesting that the disorder is genetically heterogeneous; higher functioning individuals with autism may arise from separate genetic mechanisms that lower functioning ones. If true, this will make the detection of linkage and association much more difficult.     

Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 region

Genetic studies indicate that chromosome 7q is likely to contain an autism susceptibility locus (AUTS1). We have followed a positional candidate gene approach to identify the relevant gene and report the analysis of four adjacent genes localised to a 800 kb region in 7q32 that contains an imprinted domain: PEG1/MEST, COPG2, CPA1 and CPA5-a previously uncharacterised member of the carboxypeptidase gene family. Screening these genes for DNA changes and association analysis using intragenic single nucleotide polymorphisms (SNPs) provided no evidence for an etiological role in IMGSAC families. We also searched for imprinting mutations potentially implicated in autism: analysis of both DNA methylation and replication timing indicated a normal imprinting regulation of the PEG1/COPG2 domain in blood lymphocytes of all patients tested. The analysis of these four genes strongly suggests that they do not play a major role in autism aetiology, and delineates our strategy to screen additional candidate genes in the AUTS1 locus.