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Christopher S von Bartheld, Andrea Agarwal, Cheng-yuan Feng, Austin Christensen, Dan Wen, Kellie Cassinelli, Brian Kirkpatrick, L. Alan Johnson; Molecular and Developmental Links between Strabismus and Schizophrenia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2460.
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© ARVO (1962-2015); The Authors (2016-present)
Children with exotropia have an increased risk (up to 15-70fold) of developing schizophrenia decades later. To better understand this, we asked whether signaling molecules known to be imbalanced in schizophrenia may also be dysregulated in extraocular muscles, and whether gene expression differs between medial rectus (exotropia) and lateral rectus muscles (esotropia). Given the established seasonality of birthdates in schizophrenics and differences in exotropia/ esotropia pathogenesis, we also tested whether patients with exotropia have seasonally distinct birthdates.
Samples from strabismic medial and lateral rectus muscles 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 PCR arrays surveying about 400 signaling molecules were compiled from paired comparisons (at least n=4 per condition). Birth months of 4,847 patients with either exotropia or esotropia were compiled, normalized to a matched control group, analyzed with a chi square test, and compared with published data from cohorts of patients with schizophrenia.
Ten known biomarkers for schizophrenia were significantly imbalanced in strabismic medial rectus muscles (CTGF, CXCR4, IL7, IL10R, MMP2, NRG1, NTRK2, TNF, TNFR, VEGFA, p<0.05). Most changes in gene expression of signaling molecules were similar between the two horizontal muscles, except for AKT1, BDNF, ERBB2, MMP9 and TGFB1 (reduced in medial vs. lateral rectus). Birthdates of patients with exotropia (but not esotropia) showed a pronounced peak (chi-square test, p=0.001) in summer months, which matches data reported for schizophrenics with negative symptoms.
We found that ten biomarkers for schizophrenia were significantly dysregulated in strabismic medial rectus muscles. However, most of these were similarly dysregulated in strabismic lateral rectus muscles (esotropia), and thus lacked specificity for a link between exotropia and schizophrenia. These altered gene expressions verify molecular changes in strabismic muscles. The seasonality of birthdates indicates that exotropia may relate to a distinct population among schizophrenics, those with negative symptoms, and supports the conclusions derived from twin studies that exotropia is associated with environmental influences during development more than esotropia.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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