Schizophrenia is a leading public health problem worldwide. Discovering genes that confer susceptibility to it is an important priority, as this may lead to the development of effective modalities of prevention and treatment. Although data from family, twin, and adoption studies suggest a genetic basis to schizophrenia, and several chromosomal regions have been linked to it, cloning susceptibility genes has been elusive. A specific and overarching pathophysiology of the disease has also been elusive, but evidence from neuroimaging and neuropathological studies converges to suggest that abnormal neurodevelopment may be a cause. In recent years, the biological events underlying neurodevelopment have begun to be uncovered, and several molecules that are involved in this process have been identified. One of these is neurogenini, which is involved in neuronal determination, specification of the molecular phenotype of neurons, and regional patterning of the cerebral cortex and thalamus. The gene for neurogenini is located on chromosome 5q, which has been implicated in several linkage studies of schizophrenia, including the Irish Study of High Density Schizophrenia Families (ISHDSF), which we propose to study. It is located very close to some of the most highly linked markers in this region. We propose to perform an association study of neurogenin1 and schizophrenia. As there are no known sequence variants, we propose to sequence this gene in 25 schizophrenics from the ISHDSF. We then intend to test any variants that are discovered for association with the disease. To do this, we plan to genotype all triads consisting of two parents and one affected offspring in the ISHDSF, supplemented by an additional triad collection currently underway in Ireland. We will use the transmission disequilibrium test, which determines Wan allele is transmitted to an affected offspring more often that expected by chance, to test for association and linkage. We also propose to test whether any of the variants modifies any of the clinical features of the disease. To do this, we plan to regress symptom scores on three factors as well as individual symptoms onto the transmission status of the allele, using logistic regression. If there are resources left over, we plan to genotype 400 normal controls and perform a case-control analysis using a chi-squared test to confirm any suggestive findings.
| Docherty, Anna R; Moscati, Arden A; Fanous, Ayman H (2016) Cross-Disorder Psychiatric Genomics. Curr Behav Neurosci Rep 3:256-263 |
| Docherty, Anna R; Bigdeli, T Bernard; Edwards, Alexis C et al. (2015) Genome-wide gene pathway analysis of psychotic illness symptom dimensions based on a new schizophrenia-specific model of the OPCRIT. Schizophr Res 164:181-6 |
| Fanous, Ayman H; Chen, Xiangning; Wang, Xu et al. (2007) Association between the 5q31.1 gene neurogenin1 and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 144B:207-14 |
