Abstract
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.
Highlights
The decade will see the fruits of population-scale sequencing programmes, much of which will be aimed at understanding the genetic origins of disease
We need to understand the spectrum of genetic variability in the healthy, and whole-genome datasets of healthy controls will be essential to identify genetic variation unrelated to disease[31]
This report describes the first data release of the Medical Genome Reference Bank (MGRB) comprising 2570 individuals; the MGRB will grow in time to contain sequence and phenotype data of 4000 healthy elderly Australians
Summary
Compared to a population of younger individuals (the ASRB cohort, median age 40; Supplementary Fig. 8), the MGRB, despite being ascertained on the basis of healthy ageing, was still associated with shorter telomere lengths, increased somatic mutation burden, and decreased Y chromosome and mitochondrial copy number (Table 3). ND, not determined due to data use agreement constraints (MGRB) cohorts (5 likelihood ratio tests on linear fits, Holm correction, all p < 0.003), while the rate of change of the two aged cohorts was consistent across all measures (5 likelihood ratio tests, Holm correction, all p > 0.28) Taken together, these results are suggestive of altered kinetics of age-related somatic mutation in the elderly compared to younger populations, we note longitudinal measurements will be necessary to definitively establish this relationship. This revealed that men with an mtDNA copy number in the lowest 5% for their age have the same grip strength as men with average mtDNA levels, but who are 2.5 years older (Fig. 3i)
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