Major genetic breakthrough in understanding schizophrenia

An international consortium of scientists, including researchers from the University of Western Australia (UWA), has made a major breakthrough in understanding the genetic basis of schizophrenia - a complex mental disorder which affects about 1% of people over their lifetime, leading to prolonged or recurrent episodes that severely impair social functioning and quality of life.

Over 175 scientists from 99 institutions across Europe, the USA and Australia contributed to the genome-wide association analysis, which identified 22 risk loci for schizophrenia; 13 of which are new, and one which was previously implicated in bipolar disorder. Their results were published in the journal Nature Genetics.

“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,” the study authors wrote. They said their results provide deeper insight into the genetic architecture of schizophrenia and provide a pathway to further research.

Winthrop Professor Assen Jablensky, director of UWA’s Centre for Clinical Research in Neuropsychiatry (CCRN) at Graylands Hospital, and Professor Luba Kalaydjieva, of the UWA-affiliated Western Australian Institute for Medical Research (WAIMR), led the UWA research team which took part in the study.

Professor Jablensky said that while a strong genetic component in the causation of schizophrenia was well established, the role of specific genes and the mechanisms of their regulation had 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’,” Professor Jablensky said.

Recent technological advances, enabling efficient coverage of the entire human genome with millions of single nucleotide polymorphisms (SNPs) as genetic markers, had given rise to a new generation of genome-wide association studies (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,” Professor Jablensky said.

As the study authors explain, the international, multistage GWAS for schizophrenia began with “a Swedish national sample (5001 cases and 6243 controls) followed by meta-analysis with previous schizophrenia GWAS (8832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7413 cases, 19,762 controls and 581 parent-offspring trios)”.

Professor Jablensky said the GWAS datasets were “contributed by the international Psychiatric Genomics Consortium (PGC) - which includes the UWA research team”. The collection came from 19 research centres and consortia across Europe, Australia and the USA, with WA’s case-control sample consisting of 893 schizophrenia patients and controls.

The study estimates that a total of 8300 SNPs contribute to the risk for schizophrenia and account for at least 32% of the variance in liability. Many of these SNPs, noted Professor Jablensky, “are located on a molecular pathway involved in neuronal calcium signalling, which suggests a novel pathogenetic link in the causation of schizophrenia and possibly other psychotic disorders”.

He said ongoing and future studies by the UWA research team would aim to further refine the genetic analyses of the WA schizophrenia study (which at present includes 1259 persons), and to test neurobiological hypotheses about the treatment responses of genetically defined subsets of patients.

In terms of the WHO’s ‘global burden of disease and disability’ index, schizophrenia ranks among the top 10 disorders, along with cancer, heart disease, diabetes and other non-communicable diseases.