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Genetics and Pharmacogenetics of Schizophrenia: Recent Progress

Genetics and Pharmacogenetics of Schizophrenia: Recent Progress

Figure 1FIGURE 1: MC4R single nucleotide polymorphisms rs489693 genotype and a...
Figure 2FIGURE 2: Dose adjustments according to CYP2D6 phenotypes. The dose re...

Schizophrenia is a complex and debilitating chronic mental illness, and genetic factors play a major role in its etiology and development. Traditional genetic studies estimated the heritability of schizophrenia to be 70% to 90%.1 With the rapid advance of genomic technologies, the past decade has seen an explosion of genetic studies in schizophrenia, which opened new doors for our understanding of the molecular mechanisms in this brain disease. Some experts consider these developments to signal the advent of personalized medicine.2 With our newfound knowledge of the human genome, treatment may be increasingly tailored to the individual.

This article reviews some of the most recent findings in genetics and pharmacogenetics of schizophrenia—especially those with clinical implications.

Risk genes of schizophrenia

Researchers initially hoped to find just one or a few genes predominantly responsible for schizophrenia. However, recent studies have demonstrated that many genes may be involved in susceptibility to schizophrenia (polygenic), such as the MHC (major histocompatibility complex) region on chromosome 6, MIR137 (microRNA 137), ZNF804A (zinc finger protein 804A), DISC1 (disrupted in schizophrenia 1), and DTNBP1 (dystrobrevin binding protein 1).

Most recent reports from the Psychiatric Genomics Consortium suggest that the number of genetic loci that attain genome-wide significance in association with schizophrenia is between 50 and 100 and that these loci are distributed across many genes or genomic regions.3 In addition, any one particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders, such as bipolar disorder (a phenomenon also known as “pleiotropy”).

 

A recent study found that 4 genomic loci reached genome-wide significance in a sample of 33,000 patients who had 5 psychiatric disorders (autism, schizophrenia, bipolar disorder, MDD, and ADHD) and 27,000 controls, which suggests overlaps in the genetic architecture of different mental illnesses.4 Two of these loci are voltage-gated calcium channel genes—CACNA1C and CACNB2—which supports the idea that calcium channel signaling may be a common pathway for all major mental disorders.

Our understanding of how some genes influence the risks of schizophrenia has evolved in the past decade. An example is the discovery of the DISC1 gene. Originally found in a linkage study in a Scottish family cohort, a translocation on chromosome 1 was found to be highly correlated with schizophrenia.5 This translocation directly disrupts the

DISC1 gene. The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.6

Naturally, the disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes and significantly increases susceptibility not only for schizophrenia but also for bipolar disorder and depression. Despite advances in our understanding of the biology of DISC1, however, large case-control studies have not found a consistent association between DISC1 and schizophrenia.7 One possibility is that DISC1 pathology is representative of a subtype of schizophrenia that is not prevalent among the general population, therefore preventing large-scale epidemiological studies from find-ing evidence to support the role of DISC1 in schizophrenia.

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