Symptoms of schizophrenia most commonly begin to creep up in young adulthood. Although genetics play a major role in this complex disorder, narrowing down the search for the genes involved has proven frustratingly difficult. Risk loci identified by genome-wide association studies (GWAS) may contain several genes, making it unclear which of these contribute to pathology. Risk genes may even reside outside these loci if they are affected by regulatory elements in a risk locus. In the December issue of Genetics, Lin et al. report a new computational approach to parsing the challenging data on genetic variants that predispose to the disorder.

To determine which gene in a GWAS risk locus increases vulnerability to schizophrenia, the team used predictive features of schizophrenia risk genes derived from 56 genes with very strong evidence of being linked to the disorder. And to track down contributing genes that lie outside risk loci, their analysis included gene regulatory information, such as enhancer-promoter connections identified by the ENCODE and FANTOM5 projects. This approach identified many previously unknown risk genes, some of which are involved in processes related to schizophrenia, such as neural plasticity and synaptic transmission. Some other risk genes the researchers found are also linked to autism, a neurodevelopmental disorder with a few characteristics that overlap with schizophrenia.

The researchers also noticed an interesting pattern in the tissue types that express the risk genes. Unsurprisingly, a large number of the genes identified by the analysis are expressed in the central nervous system. But one in four of these genes are not, which implies that processes outside the brain contribute to the pathogenesis of schizophrenia. Consistent with other research that suggests immune dysfunction is involved in schizophrenia, many of these risk genes are highly expressed in B-c and T lymphocytes.

By analyzing the expression of the risk genes at different points in brain development using RNA-seq data from BrainSpan, the group also discovered a relationship between the risk genes’ strength of association with schizophrenia and the timing of their expression in the brain. The most strongly schizophrenia-associated genes were more often transcribed in the late stages of brain development (between 8 and 40 years), while less strongly associated risk genes were active during early or middle periods of brain development. This is consistent with the fact that schizophrenia most often presents in late adolescence or early adulthood.

The next steps are to understand how these genes might be related to development of schizophrenia. Determining their roles in the disorder could help reveal more about the mechanisms of pathogenesis. Such insights could also inspire new drug treatments—a necessity because not all patients respond adequately to medication, and existing drugs often have severe side-effects, such as obesity and potentially permanent movement disorders. For the nearly one percent of the United States population affected by schizophrenia, who often require lifelong medication, further study of the risk genes identified by this research to develop better treatments is essential.

CITATION:

Lin, J.; Cai, Y.; Zhang, Q.; Zhang, W.; Nogales, R.; Zhang, Z. Integrated Post-GWAS Analysis Shed New Light on the Disease Mechanisms of Schizophrenia.
GENETICS, 204(4), 1587-1600.
DOI: 10.1534/genetics.116.187195
http://www.genetics.org/content/204/4/1587

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Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.

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