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Austin J Christensen, Andrea B Agarwal, Cheng-yuan Feng, Dan Wen, L. Alan Johnson, Christopher S von Bartheld; Evidence for a Novel Genetic Link between Strabismus and Schizophrenia. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1330.
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© ARVO (1962-2015); The Authors (2016-present)
Children with ocular misalignment (specifically exotropia) have a greatly increased risk of developing schizophrenia decades later, suggesting an overlapping genetic predisposition for both diseases. The association of schizophrenia with exotropia but not esotropia suggests that the two relevant rectus muscles (medial and lateral) differ in their susceptibility to schizophrenia-related gene products. We here determined (1) which genes that encode signaling molecules are differentially expressed between strabismic and normal human extraocular muscles, (2) how many of these genes overlap with biomarkers or predisposing genes for schizophrenia, and (3) which of these genes are differentially expressed between medial and lateral rectus muscles.
Strabismic lateral and medial rectus muscle samples were obtained during corrective surgeries according to IRB-approved protocols; normal samples were obtained from deceased organ donors. Consistent gene expression differences of 2-fold or more on targeted or customized PCR arrays were compiled from paired comparisons (n=4 per condition). We selected 84 genes of interest based on known risk factors for schizophrenia.
(1) Among 381 genes encoding signaling molecules, 22 were dysregulated in strabismic medial rectus muscle when compared with normal medial rectus muscle. (2) Among those 22 genes, almost half (10) were biomarkers for schizophrenia. (3) Among the 84 schizophrenia-related genes, 19 (=22.6%) were differentially expressed in the medial rectus muscle, including cytokines, growth factors and their receptors, and downstream signaling pathways (AKT1, BDNF, BMP4, CNTF-R, ERBB2, MMP9, NGF, NOTCH1, NTRK1, OSM, OLIG2, and multiple interleukins or their receptors).
Our data establish a molecular link between exotropia and schizophrenia. This suggests that a combination of defects in signaling molecules is relevant in the pathogenesis of both diseases. Differences between medial and lateral rectus muscles in the susceptibility to imbalanced signaling molecules may explain the previously mysterious specific association between exotropia (but not esotropia) and schizophrenia. The new findings may guide the design of selective, muscle type-specific treatments of strabismus, as well as enable the creation of a customized PCR array that can predict the risk of schizophrenia 20 years prior to any symptoms, and possibly its prevention.
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