Breakthrough – Genetic basis for schizophrenia

A consortium of scientists from 20 countries has made a major breakthrough in understanding the genetic basis of the debilitating disorder schizophrenia. More than 175 scientists from 99 institutions across Europe, the US and Australia contributed to a genome-wide ‘association analysis’, which identified 13 new risk loci for schizophrenia.

In a paper published in the journal Nature Genetics, the researchers write that the results provide deeper insight into the genetic architecture of schizophrenia than ever before achieved, and provide a pathway to further research.

“For the first time, there is a clear path to increased knowledge of the etiology of schizophrenia through the application of standard, off-the-shelf genomic technologies for elucidating the effects of common variation,” they say.

Schizophrenia is a complex mental disorder that affects about 1% of people over their lifetime, leading to prolonged or recurrent episodes that severely affect social functioning and quality of life.

In terms of the ‘global burden of disease and disability’ index, developed by the World Health Organization, it ranks among the top 10 disorders, along with cancer, heart disease, diabetes and other non-communicable diseases.

The researchers say that while a strong genetic component in the causation of schizophrenia had been well established, the role of specific genes and the mechanisms of their regulation remained largely unknown.

Until recently, results of genetic linkage and association studies could explain only a small fraction of the estimated heritability of the disorder and of its ‘genetic architecture’.

But recent technological advances, enabling efficient coverage of the entire human genome with millions of single nucleotide polymorphisms, called SNPs, as genetic markers, had led to a new generation of genome-wide association studies, or GWAS, which trace the DNA differences between people affected with the disease and healthy control individuals.

“Since the effects of individual SNPs are quite tiny, their reliable measurement requires very large samples of adequately diagnosed patients and controls,” the researchers say.

“This study reports on a major breakthrough in the understanding of the genetic basis of schizophrenia, achieved through meta-analysis of GWAS datasets contributed by a large international psychiatric genomics consortium.”

A case-control sample consisting of 893 schizophrenia patients and healthy controls was part of a collection of 21,246 schizophrenia cases and 38,072 controls from 19 research centres and consortia across Europe, Australia and the US.

The study found that a total of 8,300 SNPs contributed to the risk of schizophrenia and accounted for at least 32% of the variance in liability.

A particularly important result was that many of these SNPs were located on a molecular pathway involved in neuronal calcium signalling, suggesting a novel pathogenetic link in the causation of schizophrenia and possibly other psychotic disorders.

Ongoing studies aim to further refine the genetic analyses and to test neurobiological hypotheses about the treatment responses of genetically defined subsets of patients.