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.
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.
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