Molecular Genetics of the Psychosis Phenotype

Abstract

Objective Relative to recent successes in elucidating the genetic mechanisms associated with complex diseases including macular degeneration, Type II diabetes, heart disease and cancer, molecular genetic approaches to psychiatric illness have met with more limited success. While factors such as small allelic effects, allelic heterogeneity and variation in population sub-structure have received considerable attention in attempt to explain the paucity of significant results in psychiatric genetics, significantly less focus has been directed towards phenotypic factors. Method Data derived from molecular genetic studies of the psychosis phenotype in patients with a range of psychiatric illnesses are reviewed. Results Available data suggest that genes do not respect the boundaries of the current diagnostic system but may confer risk for symptom-based phenotypic variation that traverses those boundaries. Conclusions Molecular genetic studies offer convincing evidence for a relation between genetic variation and symptom-based phenotypic variation within psychiatric illness. These data may provide novel insights into the pathophysiology of schizophrenia and other related disorders. The exploration of relationships between genetic variation and symptom variation that traverses traditional diagnostic boundaries may ultimately lead to more refined classification systems that more closely reflect the genetic etiology of psychiatric illness.

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

“…Family history is considered one of the strongest risk factors for primary psychosis [16], with a heritability (i.e., the degree to which a phenotype, in this case a disorder, is genetically determined, calculated by regression-correlation analyses among close relatives) of schizophrenia estimated around 79-81% and a similar proportion in other disorders of the spectrum [17,18]. In particular, for close biologic relatives of patients with schizophrenia [13,19,20] was demonstrated a 7.5-fold higher risk for the development of primary psychosis [21] and studies on monozygotic twins [13,19,20] showed a concordance rate of approximately 50% [20,22].…”

“…The possible role of the product of gene loci associated with a higher risk of developing primary psychosis are described in Table 1 [17,18,22,42,43]. Genes were grouped according to the main function of their product.…”

“…The genes presented are among the most studied and reported in different meta-analyses or systematic reviews [17,18,22,42,43]. To facilitate consultation of the table, we have divided these genes in relation to their structure, localization, and main function (first column).…”

“…Due to the late onset of rheumatoid arthritis, is has been suggested that this relationship can be partly explained by an under-diagnosis, caused by a limited life expectancy and worse health care in individuals with psychosis [30]. However, a specific MHC class II DRB1 gene variant, namely the HLA-DRB1*04, has been associated with both an increased risk of rheumatoid arthritis and a reduced risk of developing schizophrenia [17,18,30], suggesting that a common immunogenetic background may promote the autoimmune disorder and protects from the mental one.…”

Perinatal Asphyxia in Rat Alters Expression of Novel Schizophrenia Risk Genes

“…However, the process of asphyxia may also compromise other neural systems. Accordingly, we have previously found that expression of neuregulin 1 ( NRG1 ), a schizophrenia risk gene ( DeRosse et al, 2012 ), is significantly decreased in asphyxia-induced rats ( Wakuda et al, 2015 ). The protein encoded by NRG1 plays a role in regulation of synaptic plasticity and neurotransmission ( Mei and Xiong, 2008 ).…”