Genetic Strategies for Schizophrenia

Florence Thibaut
European Psychiatric Review, 2010;3(1):30-34
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Abstract

Schizophrenia is a complex multifactorial and polygenic disease with an overall heritability of 63–85%. Taking into account the low correlations between genotype and phenotype and considering the difficulties encountered with linkage analyses in complex diseases, several teams have chosen alternative strategies to identify candidate genes, such as the endophenotype strategy or the study of chromosomal aberrations associated with psychotic symptoms. The genes identified so far from both traditional mapping, copy number variation (CNV) analysis and other strategies point to several biological pathways: the integrity of the synapse (neurexin 1, neurogranin, etc); the wnt/GSK3 signalling pathway (DISC1, TCF4, etc.) and GRIK4 or NPAS3, which are involved in functions such as neurogenesis in the brain; glutamatergic signalling (NRG1, DTNBP1, PRODH, D-amino acid oxidase activator, etc); the dopaminergic system (COMT, DRD3, etc); and the major histocompatibility complex. These findings are consistent with current developmental and biological hypotheses about psychosis. Genetic studies should also consider the potential for interactions between multiple loci at the same or at different genes (epistasis) or for epigenetics (DNA and chromatin modifications that play a critical role in regulation of various genomic functions) and, finally, for gene–environment interactions.
Keywords
Genetics, schizophrenia, endophenotypes, chromosomal abnormalities, linkage studies, association studies
Disclosure The author has no conflicts of interest to declare.
Received: August 31, 2009 Accepted December 14, 2009
Correspondence: Florence Thibaut, Psychiatry Department, University Hospital Nicolle, 1 rue de Germont 76031, Rouen, France. E: Florence.Thibaut@chu-rouen.fr

Schizophrenia is a complex multifactorial and polygenic disease. Although family, twin and adoption studies have consistently suggested that genetic factors play an important aetiological role in schizophrenia, until now very little has been known about the nature and number of these genetic factors. The overall heritability of the disease is 63–85%. In this article we will review the limitations of the traditional methods used in the search for genetic risk factors and discuss alternative strategies.

Linkage Studies – Limitations

Linkage analysis, which seeks to localise a chromosomal region associated with the transmission of a disease within families, and ultimately the responsible gene, may be very difficult in multifactorial diseases such as schizophrenia. During recent years, numerous linkage claims have been made with moderate logarithm of the odds (Lod) scores. In many cases in which an attempt has been made to replicate the linkage claim, the original positive finding has not been replicated. Linkage analysis in schizophrenia is problematic for several reasons: uncertainty about clinical status in relatives; genetic heterogeneity may be substantial; penetrance of susceptibility genotypes may be incomplete (by interacting with the environment, the genotype [either biological or psychosocial] produces a clinical phenotype meeting the diagnostic criteria for the disorder, a subclinical phenotype or a symptom-free phenotype); phenocopies are subjects who may meet the diagnostic criteria but do not have the genotype of the disorder; misspecification of the genetic model may strongly affect the results of multipoint linkage; and there are few large families with multiple affected individuals (structural variants that cause schizophrenia may also abolish fertility and decrease the number of Mendelian families).1

Although sibling pairs linkage studies avoid some of the problems encountered in family-based linkage analysis, such as the estimation of penetrance, the method has its own limitations and is most powerful under conditions of moderate genetic heterogeneity. Then, a large number of families has to be studied before a reliable linkage finding can be obtained and replicated.

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