Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.

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Circular RNAs (circRNAs) are a covalently closed subclass of non-coding RNA molecules formed by back splicing of linear precursor RNA. These molecules are relatively stable and particularly abundant in the mammalian brain and therefore may participate in neural development and function. With the emergence of circRNAs activity in gene regulation, these molecules have been implicated in several biological processes, including synaptic plasticity, and we therefore suspect they may have a role in neurobehavioral disorders. Here, we profile cortical circRNAs expression in 35 postmortem cortical gray matter (BA46) schizophrenia and a non-psychiatric comparison group, using circRNA enrichment sequencing. While more than 90,000 circRNAs species were identified in the dorsolateral prefrontal cortex (DLPFC), we observed lower complexity and substantial depletion in subjects with the disorder. Although circRNAs expression was independent of their host gene transcription, alternative splicing rates were lower in samples from cases compared to controls. Gene set analysis of differentially expressed circRNAs host genes revealed significant enrichment of neural functions and neurological disorders. Many of these depleted circRNAs are also predicted to sequester miRNAs that were shown previously to be increased in the disorder, potentially exacerbating the functional impact of their dysregulation through posttranscriptional gene silencing. While this is the first reported exploration of circRNAs in schizophrenia, there is significant potential for dysregulation more broadly in other major mental illnesses and behavioral disorders. Given their capacity for modulating miRNA function, circRNA may play a significant role in the pathophysiology of disease and even be targeted for therapeutic manipulation.