Genetically associated brain transcriptome alterations may contribute to diagnostic variation among classes of mental illnesses, according to results published in Neuropsychopharmacology.

Researchers from the National Institute of Mental Health Intramural Research Program studied 200 postmortem brains for differential expression on the basis of schizophrenia (n=46), bipolar disorder (BD; n=39), major depressive disorder (MDD; n=54), or healthy controls (n=61).

Compared with controls, transcript-level alterations were greatest among schizophrenia (n=452), followed by BD (n=359), and MDD (n=283) samples. Differences of both genes and transcripts were observed for 21 genes compared with BD, 18 with schizophrenia, and 3 with BD samples. Gene-only differences were detected among 21 genes compared with BD, 5 with schizophrenia, and 4 with MDD.


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Compared between patient groups, the greatest differences were observed between schizophrenia and BD (transcript only: n=442; gene only: n=49; gene and transcript: n=24), followed by schizophrenia and MDD (transcript only: n=281; gene only: n=6; gene and transcript: n=3) and BD compared with MDD (transcript only: n=262; gene only: n=3; gene and transcript: n=2).

Variation in loci which altered splicing were enriched among case-control (n=368; odds ratio [OR], 2.2; P <10-16) and case-case (n=335; OR, 2.5; P <10-16) comparisons. These splice-related variants were significantly enriched for their contribution to the heritability of schizophrenia (2.1; P =3.3E-5) and BD (1.7; P =.02) but were not enriched for MDD (1.2; P =.38).

The expression-related variants were observed to be significantly enriched for their contribution to heritability of schizophrenia (1.7; P =9E-5) but not for BD (1.3; P =.13) or MDD (0.8; P =.41). After correcting for splice variants, expression variants were no longer significantly enriched for the heritability of schizophrenia (1.16; P =.54).

Among rare variants (<100 mean count/sample), 269 had significant differential expression (<5% false discovery rate), indicating they may be functionally relevant. These variants were associated with synapse formation, cell junctions, and heterotrimeric G-protein complexes.

This study was limited by its low sample sizes and inherent difficulties of interpreting expression data derived from postmortem tissues which have risk for noise creating biases.

These findings suggested genetic factors have altered brain transcriptomes which contribute to diagnostic differences for broad classes of mental illnesses.

Reference

Akula N, Marenco S, Johnson K, et al. Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders. Neuropsychopharmacology. Published online February 8, 2021. doi:10.1038/s41386-020-00949-5