![]() ![]() A meta-analysis of postmortem microarray expression data found that many differentially-expressed (DE) genes were shared across psychiatric disorders such as SCZ, autism, and bipolar disorder (BD). One large postmortem study found small changes in gene expression in schizophrenia (SCZ) versus controls that seemed to reflect small differences in frequencies of alleles associated with SCZ by GWAS. ![]() Similarly, gene expression studies in postmortem brain tissue have found that expression changes in mental illnesses tend to be small and correlated across diagnoses. Genome-wide association studies (GWAS) have revealed that major psychiatric disorders share many common genetic variants that exert small effects on risk. ![]() Genetic risk factors that shape the brain transcriptome may contribute to diagnostic differences between broad classes of mental illness. Common genetic variants previously associated with disease risk were especially enriched for sQTLs, which together accounted for disproportionate fractions of diagnosis-specific heritability. Common genetic variants were associated with transcript expression (eQTL) or relative abundance of alternatively spliced transcripts (sQTL). The ~250 rare transcripts that were differentially-expressed in one or more disorder groups were enriched for genes involved in synapse formation, cell junctions, and heterotrimeric G-protein complexes. ![]() Case–case comparisons revealed greater expression differences, with some transcripts showing opposing patterns of expression between diagnostic groups, relative to controls. Case–control comparisons detected modest expression differences that were correlated across disorders. RNA obtained postmortem from 200 donors diagnosed with bipolar disorder, schizophrenia, major depression, or no psychiatric disorder was deeply sequenced to quantify expression of over 85,000 gene transcripts, many of which were rare. Here we investigate expressed genes and gene transcripts in postmortem subgenual anterior cingulate cortex (sgACC), a key component of limbic circuits linked to mental illness. Despite strong evidence of heritability and growing discovery of genetic markers for major mental illness, little is known about how gene expression in the brain differs across psychiatric diagnoses, or how known genetic risk factors shape these differences. ![]()
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