A discussion of the Progress made so far in understanding the Genetic Architecture of Schizophrenia Schizophrenia: An Elusive Complex Disorder
A discussion of the Progress made so far in understanding the Genetic Architecture of Schizophrenia Mendelian diseases conform to Mendel’s laws of genetic inheritance; segregation and independent assortment. Therefore, every pair of alleles in diploid organisms, are separated during meiosis and one allele for every trait is passed onto one of the two daughter cells, independently of all other genes. Thus, depending on the recessive or dominant status of both alleles for a gene, an individual may or may not develop a simple disorder where one gene is sufficient causality (Mendel, 1865). In Schizophrenia the prevailing genetic architecture hypothesis is that of a complex disorder composed of multiple genes, environmental and epigenetic influences, a common disease with common variants. However, the failure to identify a specific set of genes and external factors has led to much speculation on the exact nature of the disorders genetic architecture, culminating in strong support for a ‘re-branding’ to a spectrum of disorders. It is theorised that from the disorder spectrum, specific disease pathologies with confirmed causal genes could be elucidated and a final classification of a number of rare diseases would prevail. A diseases genetic architecture is the number of risk alleles, their associated effect sizes and occurrence frequency, overlaid by epistasis. To understand the genetic architecture of Schizophrenia this paper will review the disorders inheritance patterns, phenotypes, pathophysiology and neurobiological pathways, methods of genetic study, candidate genes and the various models the data support and refute.
Inheritance and Physiology
Schizophrenia has a complex mode of inheritance with a proven genetic architecture and heritability of 80%; the proportion of phenotypic variance accounted for by total genetic variance (Owen M.J. C. N., September 2005). Despite this high heritability less than 13 of probands have a familial history of Schizophrenia (Wray N. R., 2010). The lifetime risk for developing Schizophrenia is around 1% and the risk to relatives is summarised in Figure 1. Concordance rates between dizygotic twins vary from 0-28% and monozygotic twins from 41-65% (Owen M. J. O. M., 2005). The latter demonstrates the genetic significance but also confirms the role of other factors, such as environmental and epigenetic. The Schizophrenia phenotype is suspected to have significant overlap with other neuropsychological disorders such as bipolar and schizoaffective disorder. As yet it has not been possible to distinguish aetiologically significant sub groups, however the disorder is often researched based on endophenotypes of its various heterogeneous diseases processes to refine the search for genes (Owen M. J. O. M., 2005). Figure 1
The current pathophysiology of Schizophrenia comprises of reduced grey matter, white matter abnormalities, synaptic, axonal and dendritic alterations with glutamatergic and dopaminergic dysfunction presenting as both hypostimulation in the mesocortical pathway and hyperstimulation in the mesolimbic pathway (Owen M.J., 2005). Contention arises over whether these presentations are a direct result of the developing illness or a consequence of the diseases underlying pathologies. This is partially driven by the recent hypothesis that Schizophrenia is a neurodevelopmental disorder that doesn’t present until adulthood, with rare forms occurring in childhood (Owen M. J. W. H., 2009).
“All models are wrong, some are useful.” George Box, Industrial Statistician
Statistical models are applicable in revealing the architecture of a complex disorder by enabling hypotheses to be tested and models that do not fit the data to be eliminated, narrowing the genetic boundaries. Before 2005 and the advent of Genome Wide Association...
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Figure 2: Wray N. R., V. P. (2010). Narrowing the Boundaries of the Genetic Architecture of Schizophrenia. Schizophrenia Bulletin, Volume 36 No. 1:14-23.
Figure 3: Wray N. R., V. P. (2010). Narrowing the Boundaries of the Genetic Architecture of Schizophrenia. Schizophrenia Bulletin, Volume 36 No. 1:14-23.
Figure 4: Sullivan P. F. (2005). The Genetics of Schizophrenia. PLOS Medicine 2(7)
Figure 5: Sullivan P
Figure 6: Sullivan P. F. (2005). The Genetics of Schizophrenia. PLOS Medicine 2(7)
Table 1: Kim Y., Z. S. (2011). Schizoprenia Genetics: Where Next? Schizophrenia Bulletin, Volume 37, No. 3:456-463.
Table 2: Sullivan P. F. (2005). The Genetics of Schizophrenia. PLOS Medicine 2(7)
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