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Transcriptome-Wide Association Study Links Gene Expression, Mechanisms in Schizophrenia

NEW YORK (GenomeWeb) – Through a transcriptome-wide association study (TWAS), researchers have homed in on genes that contribute to schizophrenia and have begun to tease out the possible mechanisms through which they work.

Previous genome-wide association studies have linked thousands of genes to schizophrenia risk. To connect these risk genes with gene expression, researchers led by the Harvard T.H. Chan School of Public Health's Alkes Price conducted a series of analyses using both GWAS data from nearly 80,000 individuals and gene expression data from a range of tissues from almost 3,700 people. As they reported yesterday in Nature Genetics, the researchers uncovered more than 150 TWAS-significant genes, about 40 of which were linked to certain chromatin regulatory features.

"To our knowledge, this is the first TWAS for any disease to integrate analysis of gene expression, splicing, and chromatin variation, and it has moved beyond top SNPs to implicate schizophrenia-associated molecular phenotypes across the regulatory cascade," Price and his colleagues wrote in their paper.

Price and his colleagues analyzed gene expression and genome-wide SNP array data from 3,693 individuals captured by four reference panels: an RNA-seq panel collected by the CommonMind Consortium of the dorsolateral prefrontal cortex, expression array data from peripheral blood samples obtained by the Netherlands Twin Registry, expression array data from blood samples from the Young Finns Study, and RNA-seq data from adipose tissue collected by the Metabolic Syndrome in Men Study.

With each of those gene expression reference panels and summary-level statistics from the Psychiatric Genomics Consortium schizophrenia GWAS of 79,845 people, the researchers conducted their TWAS.

They identified 157 transcriptome-wide significant genes. Of these, 49 genes were significant in more than one expression panel, and 35 of them didn't overlap with a known GWAS locus. The researchers further noted hotspots of multiple TWAS associations at 33 genes. Forty-six of the transcriptome-wide significant gene associations were due to splicing events in the brain, they added.

Another recent study relied on the same schizophrenia GWAS dataset for its summary-based Mendelian randomization analysis, and Price and his colleagues noted that 12 of the 16 associations found in that study were covered in theirs and all were replicated at a nominal level and nine at transcriptome-wide level of significance.

The researchers also used published chromatin-interaction (Hi-C) data from the developing brain to determine whether these TWAS-associated genes were also linked to physical chromatin interactions there. Most of the TWAS-associated genes, they reported, were supported by three-dimensional chromatin interactions with schizophrenia SNPs in the developing brain.

Of 157 transcriptome-wide-significant genes, 42 genes also had significant chromatin TWAS associations, the researchers reported. These genes included PPP2R3C, KLC1, and MAPK3.

The expression of MAPK3, for instance, was not only linked to schizophrenia, but also to two chromatin peaks near the transcription start site. MAPK3, the researchers noted, also maps to within a copy-number variant that has been linked to both schizophrenia and autism. Other studies have indicated that changing the dose of KCTD13, a nearby gene in the region, can affect disease-related phenotypes and interact with MAPK3.

In a zebrafish model, the researchers found that overexpressing KCTD13 led, as expected, to decreased head size and number of cycling cells in the brain and adding endogenous mapk3 to those embryos rescued the phenotype. This showed, the researchers said, that MAPK3 has an effect on neurodevelopmental phenotypes and should be prioritized as a candidate for further follow up.

"Beyond specific mechanistic findings for schizophrenia, this work outlines a systematic approach to identify functional mediators of complex disease," the authors wrote.