Carleton Harrington D.O.

Portrait photograph of Dr. Carleton Harrington from at the Osteopathic Hospital of Maine in Portland, Maine.https://dune.une.edu/moa_photos/1002/thumbnail.jp

Additional file 8: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Figure S3. Activation of HSF1 in C9ORF72-ALS, FTLD, and combined ALS/FTLD patients. (a) Quantitative real-time PCR (qRT-PCR) for HSF1 target genes in the cerebellum of sporadic and C9ORF72-associated disease (n = 56 C9ORF72-ALS/FTLD, n = 42 sporadic ALS/FTLD, n = 7 controls) (one-way ANOVA with Bonferonni post-hoc test for multiple comparisons * p < 0.05, ** p < 0.01, *** p < 0.001. Note, no significant changes were detected between the sporadic cases and controls. (b) Correlation of HSF1 levels and HSF1 target gene levels in the frontal cortex and cerebellum in C9ORF72-ALS/FTLD. Spearman’s R2 values are plotted for each target gene, error bars denote 95% confidence interval, p-value < 0.0001 in all cases. (PDF 209 kb

Additional file 5: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Table S3. Genes significantly changes in RNA-seq analysis from ALS patients. (XLSX 52 kb

Additional file 7: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Table S4. Values from qPCR analysis in brain samples. (PDF 178 kb

Additional file 4: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Figure S1. Bioinformatic method comparison for gene expression analysis of C9ORF72-associated ALS and sporadic ALS (sALS) in the frontal cortex and cerebellum. (a-d) Gene density plots comparing the expression levels of differentially expressed transcripts as determined by the prior double cut-off method (|log2 fold change| ≥ 2 and p-value < 0.05) and the FDR method (FDR < 0.05), which was used in Fig. 1 and subsequent analysis. Note, no significant changes were detected in the sALS cerebellum using with FDR method. (e) Venn diagrams demonstrating considerable differences in the designated disease-associated transcripts between these bioinformatics methods in both brain regions. (f) Table of the number of differentially expressed transcripts as determined by Prudencio et al., the double cut-off method and the FDR method used here. (PDF 216 kb

Additional file 3: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Figure S5. External eye quantification scale for (GR)36 animals. For quantification of the enhancement effects of increased expression of HSF in the eye, (GR)36 animals received a score between 0 (normal eye) and 11 (extreme toxicity causing lethality). Across multiple studies control Gmr-GAL4 > (GR)36 animals receive a score between 5 and 6. (PDF 1969 kb

Additional file 6: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Figure S2. Gene networks in C9ORF72-ALS and sporadic ALS. (a) Protein-protein interaction network derived from differentially expressed transcripts in C9ORF72-ALS cerebellum. Those transcripts that are differentially expressed in both the frontal cortex and the cerebellum in C9ORF72-ALS are highlighted by dashed yellow circles, and predominantly consist of heat shock proteins and protein chaperones. (b) Protein-protein interaction network derived from differentially expressed transcripts in the sporadic ALS cortex. (PDF 164 kb

Additional file 2: of Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

Table S2. Primer sequences for PCR. (PDF 167 kb

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies