A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism.
The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for 'genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9-24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.
The Rockefeller University, Center for Clinical and Translational Science, New York, NY, USA.
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KM
Wittkowski
The Rockefeller University, Center for Clinical and Translational Science, New York, NY, USA.
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V
Sonakya
The Rockefeller University, Center for Clinical and Translational Science, New York, NY, USA.
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B
Bigio
Hochschule Koblenz, RheinAhrCampus, Joseph-Rovan-Allee 2, Remagen, Germany.
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MK
Tonn
Yale School of Medicine, Yale Autism Program, New Haven, CT, USA.
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Shic
Tuschl Laboratory of RNA Molecular Biology, The Rockefeller University, New York, NY, USA.
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Ascano
McEwen Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
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Nasca
New York University, Langone Medical Center, New York, NY, USA.
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Gold-Von Simson
D056808:Biostatistics / Q000379:methods*; D015220:Calcium Channels / Q000235:genetics; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008528:Mefenamic Acid; D049990:Membrane Transport Modulators; D015221:Potassium Channels / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics*
D015220:Calcium Channels; D049990:Membrane Transport Modulators; D015221:Potassium Channels; D017978:Receptors, Growth Factor; D008528:Mefenamic Acid