MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls.

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10-5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.

Birefringence of the human foveal area assessed in vivo with Mueller-matrix ellipsometry.

We have assessed retinal birefringence in the foveal and parafoveal regions by applying Mueller matrix ellipsometry on the human eye in vivo. Basically, a light beam passed the ocular media twice and was scattered at the fundus intermediately. Keeping the entry and exit positions on the cornea constant and varying the retinal location along a circle around the foveal center enabled us to separate the corneal and retinal components of the measured retardation. We conclude that the retina within the outer margin of the parafovea behaves as a uniaxial crystal, with its slow axis radially oriented from the fovea and a retardation of about 16 deg (to 70 deg in the corneal center). We believe that Henle's fiber layer causes retardation in this specific configuration of entrance and exit beams. The outer segments of the photoreceptors, although birefringent, have their optic axes aligned with these beams.

Corneal polarization in the living human eye explained with a biaxial model.

We have applied Mueller matrix ellipsometry to assess the change in the state of polarization of a light beam that has double passed the ocular media and is scattered at the fundus of the human eye in vivo. At several positions in the pupil plane, which together cover the area of the dilated pupil, Mueller matrices are assessed. From them the magnitude of the retardation and the orientation of the eigenvector are calculated. The properties of the retardation process are surveyed by measuring the retardation along a horizontal meridian as a function of wavelength, density of visual pigment, and location of retinal fixation. Furthermore, photographs are taken from the polarization patterns on the iris with circularly polarized light. We posit that the cornea behaves as a biaxial crystal with its fastest principal axis normal to its surface and its slowest nasally downward. The retardation of light by a model eye with such a cornea is calculated, and the results are compared with the data.

Intensity and polarization of light scattered at small angles from the human fovea.

We have investigated the equivalent reflectance and the degree of preservation of polarization of light scattered at the human fundus in vivo. Measurements are performed at various angles of incidence and reflectance with both a bleached and unbleached state of the visual pigment. In the light that is scattered from the fovea two components were distinguished. First, a wide angle scattered component whose behavior in terms of equivalent reflectance and degree of polarization is independent of the angle of incidence and reflectance. Also, its reflectance is only moderately affected by the density of the visual pigment. Second, a directional component that is most prominent in a bleached state of the visual pigment and with a central position of the entrance and exit light path. The degree of preservation of polarization is about 90% at short wavelengths and decreases to about 40% for red light. Polarization is almost invariant for the angle of incidence and reflectance and the density of the visual pigment. To explain the results a model is proposed in which the scattering of both components is assumed to take place at the same layer. A consequence of this model is that a significant amount of light leaks between the receptor outer segments.

Directionality and alignment of the foveal receptors, assessed with light scattered from the human fundus in vivo.

The directionality of the foveal receptors of four subjects is assessed with a technique based on light scattering, and a psychophysical technique. The width and orientation of the absorbance diagram (difference between the scattering diagram in a bleached and unbleached state of the visual pigment) are compared with the Stiles-Crawford function. Results show that the directionality in the scattering diagram points into approximately the same direction as the S-C function, but the width of the scattering diagram is slightly less. The alignment of foveal receptors is studied by partially bleaching the retina with oblique incidence from a nasal and temporal direction. Comparison of the absorbance diagrams with a diagram obtained with normal incident bleaching shows no significant shift in their orientations.

Ellipsometry of the human retina in vivo: preservation of polarization.

A new apparatus for in vivo retinal-scattering experiments incorporating Mueller-matrix ellipsometry is described. The basic principle is that the state of polarization of the entrance beam is modulated, after which the Stokes vector of the exit beam is assessed. Results show that nearly 90% of the degree of polarization of the entrance beam is preserved after double passage of the ocular media and retinal scattering. Changes in the state of polarization are studied in terms of a rotation around an eigenvector on the Poincaré sphere. These studies show that the type of change in the state of polarization of the totally polarized component is probably caused by a linearly birefringent process.