Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Blue Native PAGE–Antibody Shift in Conjunction with Mass Spectrometry to Reveal Protein Subcomplexes: Detection of a Cerebellar α1/α6-Subunits Containing γ-Aminobutyric Acid Type A Receptor Subtype

The pentameric γ-Aminobutyric acid type A receptors (GABAARs) are ligand-gated ion channels that mediate the majority of inhibitory neurotransmission in the brain. In the cerebellum, the two main receptor subtypes are the 2α1/2β/γ and 2α6/2β/δ subunits. In the present study, an interaction proteomics workflow was used to reveal additional subtypes that contain both α1 and α6 subunits. Immunoprecipitation of the α6 subunit from mouse brain cerebellar extract co-purified the α1 subunit. In line with this, pre-incubation of the cerebellar extract with anti-α6 antibodies and analysis by blue native gel electrophoresis mass-shifted part of the α1 complexes, indicative of the existence of an α1α6-containing receptor. Subsequent mass spectrometry of the blue native gel showed the α1α6-containing receptor subtype to exist in two main forms, i.e., with or without Neuroligin-2. Immunocytochemistry on a cerebellar granule cell culture revealed co-localization of α6 and α1 in post-synaptic puncta that apposed the presynaptic marker protein Vesicular GABA transporter, indicative of the presence of this synaptic GABAAR subtype

Molecular network generated by the Ingenuity software from the “Mouse High CPE expression sub-dataset”.

<p>Example of a molecular network generated by Ingenuity from the “Mouse High CPE expression sub-dataset (>90^th P)” of the microarray analysis. For explanation of symbols on the diagrams see legend <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083345#pone-0083345-g002" target="_blank">Figure 2</a>. The genes <i>PFKL</i>, <i>PFKM</i> and <i>PFKP</i> were previously implicated in glucose metabolism and <i>CA2</i>, <i>CA12</i> and <i>CA14</i> were attributed to diseases with disturbed lipid and/or glucose metabolism and are involved in CSF production. These genes are indicated bold in the Figure. The main functionalities given by Ingenuity for this entire molecular network are ‘Carbohydrate metabolism, ophthalmic disease and metabolic disease’.</p

Clathrin-mediated endocytosis signaling pathway identified by the Ingenuity software in the “Mouse High CPE expression sub-dataset”.

<p>This is one of the canonical pathways that contained statistically significantly more genes than expected by chance in the group of genes that are highly expressed in the mouse CPE. Gray fields indicate their presence in the “Mouse High CPE expression sub-dataset (>90^th P)”; uncolored genes are added by the Ingenuity software to show the entire standard pathway. Solid lines between molecules indicate direct physical relationships between molecules (such as regulating and interacting protein domains). Abbreviations of gene names are according to standard abbreviations used in GenBank. As shown, the majority of genes of this pathway are highly expressed in the mouse CPE.</p

A Revision of the Section of Chemung Rocks Exposed in the Gulf Brook Gorge at LeRoy, in Bradford County, Pennsylvania

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Molecular network generated by the Ingenuity software from the “Mouse High CPE expression sub-dataset”.

<p>Example of a molecular network generated by Ingenuity from the “Mouse High CPE expression sub-dataset (>90^th P)” of the microarray analysis. For explanation of symbols on the diagrams see legend <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083345#pone-0083345-g002" target="_blank">Figure 2</a>. In this network there are genes involved in maturation of embryonic stem cells, generation of dopaminergic neurons and survival of RPE cells (<i>BCL2L1</i>), size of the eye (<i>AES, TLE1</i>), development of neural crest (<i>MSX1</i>), morphogenesis of cartilage tissue and middle ear (<i>MSX1</i>), and apoptosis of the embryoblast (<i>TAF10</i>). These genes are indicated bold in the Figure. The main functionalities given by Ingenuity for this entire molecular network are ‘Gene expression, embryonic and organ development’.</p

Expression of epithelial junction genes in human and mouse CPE.

<p>This diagram illustrates the distribution of expression of epithelial junction genes in human and mouse CPE, subdivided in the four sub-datasets (very low (<10^th P); low (10–50^th P); moderate (50–90^th P); and high (>90^th P); see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083345#s2" target="_blank">Methods</a>). On the x-axis, the four different expression subgroups are displayed, on the y-axis the number of genes. The black solid lined circles contain epithelial junctions expressed in human CPE expression data and the grey dotted lined circles include those of the mouse CPE. The epithelial junction genes showed overlap in expression category between human and mouse CPE, and none of them showed a difference in expression more than one sub-dataset between human and mouse. For example, the genes CDH1 and CDH3 were highly expressed in human CPE and moderately in mouse CPE, whereas the genes CLDN2 and CLDN3 were highly expressed in mouse CPE and moderately in human CPE and the gene CTNNB1 was highly expressed in both human and mouse CPE.</p

Molecular network generated by the Ingenuity software from the “Human High CPE expression sub-dataset”.

<p>Example of a molecular network generated by Ingenuity from the “Human High CPE expression sub-dataset (>90^th P)” of the microarray analysis. For explanation of symbols on the diagrams see legend <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083345#pone-0083345-g002" target="_blank">Figure 2</a>. This network contains several genes that code for proteins involved in transport of specific biomolecules, namely <i>CYTB</i> and <i>UQCR11</i> (transport of H+), <i>MUT</i> and <i>NFE2L1</i> (transport of glutathione and carnitine), <i>VDAC3</i> (transport of adenine) and <i>C1QBP</i> (transport of hyaluronic acid and lactic acid). The genes mentioned are indicated bold in the Figure. The main functionalities given by Ingenuity for this entire molecular network are ‘Hereditary disorder, metabolic disease and molecular transport’.</p

CPE gene expression of ion channel proteins implicated in CSF production.

<p>Expression levels of genes coding for ion channel proteins implicated in cerebrospinal fluid (CSF) production in healthy human and mouse CPE. We ranked the genes by expression level and assigned percentile ranks (P). Next, we formed four groups: high (H) expression (expression >90th P), moderate (M) expression (50–90th P), low (L) expression (10–50th P) and very low (VL) expression (<10th P). This means that a gene in the high expression group (>90th P) has an expression intensity that falls into the highest 10% intensity values of the microarray, whereas a gene in the very low expression group (<10th P) has an expression intensity in the lowest 10% intensity values of the microarray. For genes indicated with “-”, no data were available.</p><p>Abbreviations: H1 = our gene expression data of healthy human CPE; M1 = our gene expression data of healthy mouse CPE; H2 = healthy human CPE GSE14098; M2 = healthy mouse CPE GSE23714; M3 = healthy mouse CPE GSE37098; M4 = healthy mouse CPE GSE33009.</p

Mouse specifically expressed CPE genes compared to human CPE.

<p>Mouse specifically expressed CPE genes compared to human CPE.</p