Brain Transcriptome Distinctions, Overlaps Characterized in Neuropsychiatric Conditions

NEW YORK (GenomeWeb) – New research is defining the similarities and differences between brain gene expression profiles involved in neuropsychiatric conditions such as autism spectrum disorder (ASD), schizophrenia, and bipolar disorder.

Researchers from the University of California, Los Angeles and elsewhere analyzed available array-based brain gene expression patterns for 700 individuals with ASD, schizophrenia, bipolar disorder, depression, or alcohol abuse disorder. In the process, they narrowed in on expression profiles that distinguished the conditions from one another, along with shared expression features that often reflected overlapping genetic risk SNPs in the conditions considered.

"The degree of sharing of transcriptional dysregulation is related to polygenic (single nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component," senior author Daniel Geschwind, director of UCLA's Center for Autism Research and Treatment, and his colleagues wrote. 

The team verified these patterns — and began unraveling the underlying genetic contributions to transcriptional signatures — using its own brain RNA sequence data for more than 150 individuals with ASD, schizophrenia, or bipolar disorders and heritability clues from prior genome-wide association studies. The results appeared online today in Science.

"These findings provide a molecular, pathological signature of these disorders, which is a large step forward," Geschwind said in a statement. "The major challenge now is to understand how these changes arose."

For the first stage of their analysis, he and his colleagues brought together published array-based gene expression profiles for post-mortem cerebral cortex samples for 50 individuals with ASD, 159 schizophrenia cases, 94 bipolar disorder sufferers, 87 individuals with major depressive disorder, and 17 individuals with alcoholism.

The team compared these expression patterns to one another and to expression profiles for nearly 300 non-psychiatric controls, uncovering brain expression shifts that were most pronounced in the ASD cases. The depression cases had more modest expression changes, while the bipolar disorder and schizophrenia samples fell in the middle on the brain expression spectrum. In contrast, the alcohol abuse disorder samples did not share clear expression features with the other conditions.

Such results were further supported by RNA-seq data generated using Illumina HiSeq2000 instruments on post-mortem frontal cortex samples from 53 individuals with schizophrenia, 47 bipolar disorder cases, and 53 non-psychiatric controls through the PsychEncode Consortium's BrainGVEX study. The researchers also generated RNA-seq data across four cortical brain regions in post-mortem brain samples from 53 ASD cases and two dozen unaffected controls using Illumina HiSeq 2500 instruments.

Using those data, they identified nearly 1,100 differentially expressed genes in the ASD brain samples compared to 112 differentially expressed genes in brain samples from individuals with bipolar disorder.

Again, the brain expression profiles pointed to transcriptional overlap across the three neuropsychiatric conditions, the team reported. In a series of follow-up analyses, the group began untangling the pathways and gene networks behind the shared and distinct brain expression signatures associated with the conditions, along with potential expression ties to related risk SNPs or de novo mutations.

"Our data suggest that shared genetic factors underlie a substantial proportion of cross-disorder expression overlap," the authors wrote. "Given that a minority of these relationships represent expression quantitative trait loci, most of the genetic effects are likely acting indirectly, through a cascade of developmental and cell-cell signaling events rooted in genetic risk."

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