| 1 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 117-20 |
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| PMID | 17044098 |
| Title | IGF1, growth pathway polymorphisms and schizophrenia: a pooling study. |
| Abstract | It has been hypothesized that insulin-like growth factors (IGFs) and components of the growth-hormone (GH)-IGF axis may underlie reported associations of poor fetal and childhood growth with schizophrenia. We have investigated the association of schizophrenia with 16 SNPs spanning the IGF1 gene with an inter-marker distance of approximately 2-3 kb. We also examined associations with four common functional polymorphisms of genes involved in aspects of the GH-IGF system--the IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), growth hormone (GH1), and IGF binding protein-3 (IGFBP3). The study was based on an analysis of pooled DNA samples from 648 UK and Irish cases of schizophrenia and 712 blood donor controls and of 297 Bulgarian parent offspring trios. In replicated pool analyses, none of the 16 SNPs in IGF1 nor the 4 key SNPs in the other growth pathway genes were associated with schizophrenia. SNP coverage of IGF1 was extensive, so our findings do not support a major role for IGF-I in the aetiology of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | J. Hum. Genet. 2009 Nov 54: 665-75 |
| PMID | 19834500 |
| Title | Thalamic transcriptome screening in three psychiatric states. |
| Abstract | The prefrontal cortex has been implicated in schizophrenia (SZ) and affective disorders by gene expression studies. Owing to reciprocal connectivity, the thalamic nuclei and their cortical fields act as functional units. Altered thalamic gene expression would be expected to occur in association with cortical dysfunction. We screened the expression of the entire human genome of neurons harvested by laser-capture microdissection (LCM) from the thalamic primary relay to dorsolateral prefrontal cortex in three psychiatric disease states as compared with controls. Microarray analysis of gene expression showed the largest number of dysregulated genes was in SZ, followed by major depression (MD) and bipolar mood bipolar (BP) (1152, 385 and 288, respectively). Significantly, IGF1-mTOR-, AKT-, RAS-, VEGF-, Wnt- and immune-related signaling, eIF2- and proteasome-related genes were unique to SZ. Vitamin D receptor and calcium signaling pathway were unique to BP. AKAP95 pathway and pantothenate and CoA biosynthesis were unique to MD. There are significant differences among the three psychiatric disorders in MDNp cells. These findings offer new insights into the transcriptional dysregulation in the thalamus of SZ/BP/MD subjects. |
| SCZ Keywords | schizophrenia |
| 3 | Nature 2013 Nov 503: 267-71 |
| PMID | 24132240 |
| Title | SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. |
| Abstract | Phelan-McDermid syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of autism spectrum disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-D-aspartate (NMDA) receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it. |
| SCZ Keywords | schizophrenia |
| 4 | Pharmacogenomics 2014 May 15: 951-62 |
| PMID | 24956249 |
| Title | No association between genetic or epigenetic variation in insulin growth factors and antipsychotic-induced metabolic disturbances in a cross-sectional sample. |
| Abstract | Second-generation antipsychotics (SGA) are known to induce metabolic disturbances. Genetic pathways, such as the IGF pathway could be associated with increased metabolic syndrome (MetS). Additionally, IGF2 methylation varies as a function of environmental influences and is associated with schizophrenia and MetS. The current study aims to evaluate whether genetic and epigenetic variation in genes of the IGF pathway are associated with metabolic disturbances in patients under treatment with SGAs. Cross-sectional metabolic data from 438 patients with schizophrenia spectrum disorder was analyzed. Using the Sequenom MassARRAY iPLEX(TM) platform, 27 SNPs of the IGF1 and IGF2 genes and the IGF receptors IGF1R and IGF2R were genotyped. Methylation status of seven IGF2 CpG dinucleotides was evaluated using a Sequenom MALDI-TOF spectrometer. There was a significant association between IGF2 methylation and genotype, but no significant association between genetic or epigenetic variability and metabolic parameters in the present study. |
| SCZ Keywords | schizophrenia |
| 5 | Rev Neurosci 2014 -1 25: 559-74 |
| PMID | 24778346 |
| Title | Emerging evidence of insulin-like growth factor 2 as a memory enhancer: a unique animal model of cognitive dysfunction with impaired adult neurogenesis. |
| Abstract | In the current aging society, cognitive dysfunction is one of the most serious issues that should be urgently resolved. It also affects a wide range of age groups harboring neurological and psychiatric disorders, such as Alzheimer's disease and schizophrenia. Although the molecular mechanism of memory impairment still remains to be determined, neuronal loss and dysfunction has been revealed to mainly attribute to its pathology. The discovery of neural stem cells in the adult brain that are proliferating and able to generate functional neurons has given rise to the idea that neuronal loss could be rescued by manipulating endogenous neural progenitor and stem cells. To this end, we must characterize them in detail and their developmental programming must be better understood. A growing body of evidence has indicated that insulin-like peptides are involved in learning and memory and maintenance of neural progenitor and stem cells, and clinical trials of insulin as a memory enhancer have begun. In contrast to the expectation of insulin and IGF1, the roles of IGF2 in cognitive ability have been poorly understood. However, recent evidence demonstrated in rodents suggests that IGF2 may play a pivotal role in adult neurogenesis and cognitive function. Here, we would like to review the rapidly growing world of IGF2 in cognitive neuroscience and introduce the evidence that its deficit is indeed involved in the impairment of the hippocampal neurogenesis and cognitive dysfunction in the model mouse of 22q11.2 deletion syndrome, which deletes Dgcr8, a critical gene for microRNA processing. |
| SCZ Keywords | schizophrenia |