Abstract
Schizophrenia (SCZ) and bipolar disorder are debilitating neuropsychiatric disorders arising from a combination of environmental and genetic factors. Novel open reading frames (nORFs) are genomic loci that give rise to previously uncharacterized transcripts and protein products. In our previous work, we have shown that nORFs can be biologically regulated and that they may play a role in cancer and rare diseases. More importantly, we have shown that nORFs may emerge in accelerated regions of the genome giving rise to species-specific functions. We hypothesize that nORFs represent a potentially important group of biological factors that may contribute to SCZ and bipolar disorder pathophysiology. Human accelerated regions (HARs) are genomic features showing human-lineage-specific rapid evolution that may be involved in biological regulation and have additionally been found to associate with SCZ genes. Transposable elements (TEs) are another set of genomic features that have been shown to regulate gene expression. As with HARs, their relevance to SCZ has also been suggested. Here, nORFs are investigated in the context of HARs and TEs. This work shows that nORFs whose expression is disrupted in SCZ and bipolar disorder are in close proximity to HARs and TEs and that some of them are significantly associated with SCZ and bipolar disorder genomic hotspots. We also show that nORF encoded proteins can form structures and potentially constitute novel drug targets.
Highlights
The heritability of both schizophrenia (SCZ) and bipolar disorder (BD) is ~70%—placing them among the most heritable mental health disorders [1,2,3,4], the corresponding polygenic risk scores explain only a fraction of genetic disease liability, for example, 7% in SCZ [5] relative to 64–81% heritability derived from family and twin studies
Post-mortem anterior prefrontal cortex (BA10) samples were obtained from 23 SCZ, 23 BD, and 23 control samples entries (GRCh38; 247,404 entries in Novel open reading frames (nORFs) hg19) after removal of nORFs that were in-frame with the canonical ORFs (cORFs) as determined by our classification scheme (Supplementary Figure 2A)
DHS1, transcription factors (TFs), and histone modification enrichments were found within the transcribed nORFs, and SCZ-specific loci were found enriched with transcribed and differentially expressed (DE) nORFs
Summary
The heritability of both schizophrenia (SCZ) and bipolar disorder (BD) is ~70%—placing them among the most heritable mental health disorders [1,2,3,4], the corresponding polygenic risk scores explain only a fraction of genetic disease liability, for example, 7% in SCZ [5] relative to 64–81% heritability derived from family and twin studies. SCZ and BD; pose an evolutionary-genetic paradox because they exhibit strong negative fitness effects and high heritability, yet they persist at a prevalence of ~1% across all human cultures. Past work has suggested that SCZ may be the result of humanspecific brain evolution [8, 9] and some genes associated with the disease may have undergone positive selection [10, 11]. Studies have shown that mutations beneficial for human-specific cognitive prowess may predispose an individual to SCZ [12, 13]. It is becoming increasingly clear that mutations beneficial to human cognitive abilities, including those related to disproportionately high consumption of energy by the human brain, might have been favored by natural selection and increases the risk of SCZ [13]. The origin of both these disorders could be complex and likely governed by evolutionary mechanisms that are not mutually exclusive [15]
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