Abstract
In humans, the most common genomic disorder is a hemizygous deletion of a 1.5–3 Mb region of chromosome 22q11.2. The resultant 22q11.2 deletion syndrome (22q11.2DS) can affect multiple organ systems, and most notably includes cardiac, craniofacial, and neurodevelopmental defects. Individuals with 22q11.2DS have a 20–25-fold risk of developing schizophrenia compared to individuals from the general population, making 22q11.2DS the strongest known molecular genetic risk factor for schizophrenia. Although the deleted region includes DGCR8, a gene coding for a miRNA processing protein, the exact mechanism by which this deletion increases risk is unknown. Importantly, several lines of evidence suggest that miRNAs may modulate risk for schizophrenia in other, non-22q11.2DS populations. Here we present a theory which mechanistically explains the link between 22q11.2DS, miRNAs, and schizophrenia risk. We outline the testable predictions generated by this theory and present preliminary data in support of our model. Further experimental validation of this model could provide important insights into the etiology of both 22q11.2DS and more common forms of schizophrenia.
Highlights
Microdeletion of chromosome 22q11.2 or 22q11.2 deletion syndrome (22q11.2DS) (MIM #188400/#192430) is the most common human deletion syndrome with an estimated prevalence of 1 in 4000 live births (Goodship et al, 1998)
This background effect could be as simple as a single modifier locus that interacts with the deletion to determine penetrance of schizophrenia, or it could be similar to the complicated genetic risk proposed for non-22q11.2DS mediated schizophrenia, with the potential for multiple distributed liability loci acting in concert to cause illness
Among the simulated datasets, only an average of 9.3% of the genes were identified in starBase as potential targets of two or more of the miRNAs observed to be decreased in the DiGeorge Critical Region Gene 8 (DGCR8) haploinsufficient mice, compared to the 17% observed in the real data set
Summary
Microdeletion of chromosome 22q11.2 or 22q11.2 deletion syndrome (22q11.2DS) (MIM #188400/#192430) is the most common human deletion syndrome with an estimated prevalence of 1 in 4000 live births (Goodship et al, 1998). The importance of genetic background on variable expressivity and penetrance is well known from the mouse genetics literature, where the same mutation can manifest very differently in different strains (Linder, 2006) This background effect could be as simple as a single modifier locus that interacts with the deletion to determine penetrance of schizophrenia, or it could be similar to the complicated genetic risk proposed for non-22q11.2DS mediated schizophrenia, with the potential for multiple distributed liability loci acting in concert to cause illness. Despite the small magnitude of evidence for association in the best supported SNPs and the expectation that some of these findings were due to chance allele segregations, we reasoned that these top SNPs should be enriched for real association signals We tested this possibility by a further application of our hypothesis of miRNA mediated risk for schizophrenia in 22q11.2DS.
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