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

ABSTRACT: 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.

SUBMITTER: Vardarajan BN

PROVIDER: S-EPMC3669925 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Vardarajan B N BN Eran A A Jung J-Y JY Kunkel L M LM Wall D P DP

Translational psychiatry 20130528

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 ...[more]

PMID: 23715297

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Project description:BACKGROUND:Although temperament has been recognized as an important contributor to childhood psychopathology, its role in emergent autism spectrum phenotypes is not well understood. This study examined whether toddlers with autism spectrum disorder (ASD) display temperamental vulnerabilities compared to toddlers with other developmental challenges, whether these characteristics are distinct from core autism symptoms, if they are stable over time, and if they contribute to social outcomes in preschool. METHODS:Parents of 165 toddlers with ASD, 58 nonverbal ability- and chronological age- (CA) matched developmentally delayed (DD) toddlers, and 92 CA-matched typically developing (TD) toddlers completed the Toddler Behavior Assessment Questionnaire-Supplemental (TBAQ-S) at 26 months (SD = 6; Time 1). TBAQ-S data were also available for a subset of toddlers with ASD (n = 126) at 43 months (SD = 9; Time 2). RESULTS:Compared to the DD and TD groups, toddlers with ASD exhibited vulnerabilities within the Effortful Control domain as well as the Surgency domain. They also displayed greater Negative Emotionality compared to TD peers. In the ASD group, temperamental characteristics were not concurrently related to autism severity or developmental level and individual differences were highly stable over time. Changes in Perceptual Sensitivity, Inhibitory Control, and Low-Intensity Pleasure from age 2 to 3.5 uniquely predicted autism symptom severity and adaptive social skill level at Time 2. CONCLUSIONS:Temperamental vulnerabilities in toddlers with ASD are stable over time and involve attentional and behavioral control as well as affective reactivity. They contribute uniquely to social outcomes in preschool and are likely to signal risk for developing later maladaptive attentional, affective, and behavioral symptoms. Considering biologically based dimensions may shed light on noncore facets of the early ASD phenotype that are potentially relevant to the emergence of comorbid conditions later in childhood.

Project description:BACKGROUND: HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies. METHODS: Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios. RESULTS: We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)chi2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01). CONCLUSIONS: HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.

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Dataset Information

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

Publications

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

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