| 1 | Mol. Psychiatry 2009 Jan 14: 30-6 |
|---|---|
| PMID | 18813210 |
| Title | Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2. |
| Abstract | We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Am. J. Hum. Genet. 2012 Feb 90: 175-200 |
| PMID | 22325359 |
| Title | Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. |
| Abstract | Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition. |
| SCZ Keywords | schizophrenia |
| 3 | World J. Biol. Psychiatry 2012 Dec 13: 599-604 |
| PMID | 22404656 |
| Title | FGFR2 is associated with bipolar disorder: a large-scale case-control study of three psychiatric disorders in the Chinese Han population. |
| Abstract | Repetitive linkage analyses have indicated 10q25-q26 as a shared risk region for schizophrenia (SCZ) and bipolar disorder (BPD). A genome-wide association study and follow-up recently identified a significant association between a single nucleotide polymorphism (SNP) of this region (rs17101921) and SCZ. The nearest gene to this SNP is fibroblast growth factor receptor 2 (FGFR2). We carried out a large scale case-control study to test the association between FGFR2 and three major psychiatric disorders: SCZ, BPD and major depressive disorder (MDD) in the Chinese Han population. Eight tag SNPs were genotyped using Taqman assay in 1139 BPD patients, 1112 SCZ patients, 1119 MDD patients and 1135 shared healthy controls. After correcting the multiple tests by permutation, one SNP (rs11199993), and a haplotype including this SNP, was found to be significantly associated with BPD. Potential population stratification in our samples was analyzed using 70 additional random SNPs dispersed on different chromosomes. No population stratification was detected, so our results could not be affected by this cofounding factor. Limitations of our study include incomplete coverage and insufficient power to detect association for relatively small odds ratio. Association between FGFR2 and BPD is worthy of further confirmation. |
| SCZ Keywords | schizophrenia |
| 4 | Neuroscientist 2013 Oct 19: 479-94 |
| PMID | 23343917 |
| Title | Fibroblast growth factors in neurodevelopment and psychopathology. |
| Abstract | In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology. |
| SCZ Keywords | schizophrenia |