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Mount Sinai scientists and international team shed new light on schizophrenia.

As part of a multinational, collaborative effort, researchers from the Icahn School of Medicine at Mount Sinai have helped identify over 100 locations in the human genome associated with the risk of developing schizophrenia, in the largest genomic study published on any psychiatric disorder to date, conducted with 80,000 people. The findings point to biological mechanisms and pathways that may underlie schizophrenia, and could lead to new approaches to treating the disorder, which has seen little innovation in drug development in more than 60 years.

Schizophrenia, a debilitating psychiatric disorder that affects approximately 1 out of every 100 people worldwide, is characterized by hallucinations, paranoia, and a breakdown of thought processes, and often emerges in the teens and early 20s. Its lifetime impact on individuals and society is high, both in terms of years of healthy life lost to disability and in terms of financial cost, with studies estimating the cost of schizophrenia at over $60 billion annually in the U.S. alone.

By studying the genome, the medical community are getting a better handle on the genetic variations that are making people vulnerable to psychiatric disease.  Through the wonders of genomic technology, researchers are in a period in which, for the first time, they are beginning to understand many of the players at the molecular and cellular level.

In the genome-wide association study (GWAS), the team looked at over 80,000 genetic samples from schizophrenia patients and healthy volunteers and found 108 specific locations in the human genome associated with risk for schizophrenia. Eighty-three of those loci had not previously been linked to the disorder.  Through its open and extensive worldwide data sharing policies, The Psychiatric Genomics Consortium (PGC), which led this work, is having a major impact on the understanding of schizophrenia. Without these efforts it would have been impossible to gather and analyze DNA data from enough people with and without schizophrenia.

The study implicates genes expressed in brain tissue, particularly those related to neuronal and synaptic function. These include genes that are active in pathways controlling synaptic plasticity, a function essential to learning and memory, and pathways governing postsynaptic activity, such as voltage-gated calcium channels, which are involved in signaling between cells in the brain. These newly identified loci may point to additional therapeutic targets. Cell and tissue gene-type enrichment was also used to identify domineering pathways and brain regions in the disease.

The fact that the group were able to detect genetic risk factors on this massive scale shows that schizophrenia can be tackled by the same approaches that have already transformed understanding of other diseases.  The wealth of new findings have the potential to kick-start the development of new treatments in schizophrenia, a process which has stalled for the last 60 years.

The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium, an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease. The current paper used 55 datasets from more than 40 different contributors to conduct the analysis. The DNA data from the 80,000 people used in this study represent all the data that the consortium has amassed to date. The PGC is currently genotyping over 100,000 additional people to further study schizophrenia and other psychiatric diseases, including autism and bipolar disorder.

Source:  The Mount Sinai Health System 

Manhattan plot showing schizophrenia associations.  Manhattan plot of the discovery genome-wide association meta-analysis of 49 case control samples (34,241 cases and 45,604 controls) and 3 family based association studies (1,235 parent affected-offspring trios). The x axis is chromosomal position and the y axis is the significance (–log10 P; 2-tailed) of association derived by logistic regression. The red line shows the genome-wide significance level (5 × 10−8). SNPs in green are in linkage disequilibrium with the index SNPs (diamonds) which represent independent genome-wide significant associations.  Biological insights from 108 schizophrenia-associated genetic loci.  O’Donovan et al 2014.
Manhattan plot showing schizophrenia associations. Manhattan plot of the discovery genome-wide association meta-analysis of 49 case control samples (34,241 cases and 45,604 controls) and 3 family based association studies (1,235 parent affected-offspring trios). The x axis is chromosomal position and the y axis is the significance (–log10 P; 2-tailed) of association derived by logistic regression. The red line shows the genome-wide significance level (5 × 10−8). SNPs in green are in linkage disequilibrium with the index SNPs (diamonds) which represent independent genome-wide significant associations. Biological insights from 108 schizophrenia-associated genetic loci. O’Donovan et al 2014.

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