Published: 22-01-2014 00:00 | Updated: 05-02-2014 20:05

Rare genetic mutations contribute to schizophrenia risk

In the largest exome sequencing effort within psychiatry to date, scientists at Karolinska Institutet and international collaborators provide new information about the genetic complexity underpinning schizophrenia. The study reports that schizophrenia is likely influenced by far more rare genetic mutations than previously suspected. The findings are published in the journal Nature.

Researchers have interrogated the fraction of the genome encoding all known genes using a technique termed exome sequencing. In the largest exome sequencing effort in psychiatry so far, this study used over 2,500 cases and 2,500 controls from Sweden to determine that many rare mutations across dozens of genes contribute to a persons risk of schizophrenia, rather than only a few faulty genes.

Both cases and controls have rare mutations, but there is a difference in where these mutations are located in the genome. We find an increased burden of rare disruptive mutations in certain subsets of genes, including genes coding for voltage-gated calcium ion channels and a specific neural protein complex, both of which are important for the communication between neurons, said study co-author Anna Kähler, PhD, at the Department of Medical Epidemiology and Biostatistics.

The functional mechanisms implicated by the associated gene sets, are in line with previous studies of more common genetic variants, investigated using other methods. In addition, the results of the current study support previous findings that no single variant will always lead to schizophrenia, but that genetic risk is conferred through large sets of both rare and common genetic variants.

Identifying the different constellations of genetic and environmental factors that can lead to schizophrenia will be particularly important in assessing risk or determining treatment plans on an individual basis, said co-author Sarah Bergen, PhD, Department of Medical Epidemiology and Biostatistics. This study opens a new window into the causes of this devastating disorder and brings us one small step closer to this goal.

According to the researchers, the generated sequencing data from this study forms a resource that will be invaluable to the biomedical community in continued efforts to elucidate factors that contribute to schizophrenia. Additional DNA sequencing efforts in this and other collections will play an important role in future discoveries in this field.

The lead author of the current study is Shaun Purcell, PhD, head of the Center for Statistical Genomics at Mount Sinai. The Swedish part of the study was supervised by Professor Christina Hultman of Karolinska Institutet. In addition to researchers at Karolinska Institutet and the Icahn School of Medicine at Mount Sinai, authors of this paper include researchers at the University of North Carolina, Stanley Center for Psychiatric Research at the Broad Institute, Massachusetts General Hospital, Wellcome Trust Sanger Institute, University of Edinburgh, and Harvard Medical School. The Swedish funders of this project were Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, an ALF grant from the Stockholm County Council, the Söderström Königska Foundation, and the Swedish Society for Medical Research (SSMF).


A polygenic burden of rare disruptive mutations in schizophrenia.
Purcell S, Moran J, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al
Nature 2014 Feb;506(7487):185-90