Dataset Information

Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

ABSTRACT: Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark's roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophrenia depending on normal variation (mean ± 1 s.d.) in adjusted birth size, which we use as a proxy for diametric gene-dosage variation in utero. Above-average-sized babies (weight, 3691-4090 g; length, 52.8-54.3 cm) had significantly higher risk for autism spectrum (AS) and significantly lower risk for schizophrenia spectrum (SS) disorders. By contrast, below-average-sized babies (2891-3290 g; 49.7-51.2 cm) had significantly lower risk for AS and significantly higher risk for SS disorders. This is the first study directly comparing autism and schizophrenia risks in the same population, and provides the first large-scale empirical support for the hypothesis that diametric gene-dosage effects contribute to these disorders. Only the kinship theory of genomic imprinting predicts the opposing risk patterns that we discovered, suggesting that molecular research on mental disease risk would benefit from considering evolutionary theory.

SUBMITTER: Byars SG

PROVIDER: S-EPMC4211440 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

Byars Sean G SG Stearns Stephen C SC Boomsma Jacobus J JJ

Proceedings. Biological sciences 20141101 1794

Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark's roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophre ...[more]

PMID: 25232142

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Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.

Dataset Information

Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

Publications

Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

Similar Datasets

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