Advances in understanding the etiology of schizophrenia

Abstract EN

chizophrenia is a complex disorder.

Family, twin and adoption studies demonstrate that genetic and environmental components contribute to the etiology of schizophrenia.

Environmental factors include growing up in an urban environment, immigration, cannabis usage, male gender, perinatal events and pregnancy during famines.

The genetic component seems to include genes distributed across the human genome.

Determining the genomic location and identity of schizophrenia risk genes can be done using either the methods of linkage or association.

Linkage studies utilizing genetic markers have identified a variety of genes that could be linked to schizophrenia.

However, linkage is observed on most chromosomes and covers thousands of genes with small effect sizes.

Association studies are more useful for gene identification in complex disorders with a polygenic mode of inheritance such as schizophrenia.

Genetic association studies investigate the correlation between disease status and a genetic marker in people with or without schizophrenia.

The advantage of association studies is the possibility to recruit a large sample size with enough power to detect genes of moderate effect.

The completion of the human genome project and the availability of information on more than 3.1 million genetic markers across the human genome have paved the way to conduct genome-wide association studies (GWAS).

As many as 500,000 SNPs have been tested in GWAS for association with schizophrenia.

The Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) was created with the aim to maximize sample size by combining GWAS data from multiple international research groups.

Significant schizophrenia associations were identified in 108 distinct loci.

The most significant association was in the major histocompatibility complex (MHC) on the short arm of chromosome 6.

A recent study of tens of thousands of people with and without schizophrenia has shown that the association of schizophrenia to the MHC locus was strongest at the C4 gene encoding for complement component 4.

The expression of C4 is related to “synaptic pruning”.

This biological process provides a potential etiological link between the genetic makeup and the development of schizophrenia Identifying biological mechanisms that link genetic findings to clinical manifestations of schizophrenia will help advance the diagnosis, treatment and prevention of schizophrenia.