In a world first, researchers have created a genome reference database of thousands of healthy older Australians, which has the potential to predict disease-linked gene variants more accurately than has been previously possible. The team just released the first 2,570 genomes of the Medical Genome Reference Bank (MGRB) and published their analysis, which includes several findings about health and disease, in the journal Nature Communications.
The MGRB is a collaboration led by Garvan Institute of Medical Research, Monash University’s ASPREE study, and the Sax Institute’s 45 and Up Study. The authors write that “the MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy aging.”
The data comprise whole-genome sequence (WGS) and phenotype data from elderly Australians who lived to at least 70 years of age without any history of cancer, cardiovascular disease, or dementia. The full study will comprise 4,000 individuals. For comparison, the team also performed WGS of 344 young subjects, and 273 elderly individuals with cancer. Then they conducted a broad spectrum, systematic analysis of germline and somatic variation within the nuclear and mitochondrial genomes, linking them to both chronologic age as well as frailty measures.
“By doing a comprehensive analysis of healthy individuals, we can get a much clearer understanding of which genes are and which are not linked to disease. The Medical Genome Reference Bank will provide an ideal background for the future of genomic research in Australia,” says David Thomas, Garvan Cancer Research Theme Leader and Director of The Kinghorn Cancer Centre.
This initial analysis reports MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts. Further, age-related somatic changes are correlated with grip strength in men, suggesting sequencing may also provide a biologic measure of age-related functional deterioration.
In their paper, the authors point out that “relatively little is known about the genetic determinants of ageing that account for the broad spectrum of health states observed in older people.” They also note that common variation at only a small number of loci has been consistently associated with lifespan or parental longevity. Limited by sample size, most studies have focused on single-nucleotide variants and indels, while large-scale structural variation remains unexplored. Healthy aging, is distinct from longevity, which does not account for quality of life. It is also a critical area of study, given the impact of prolonged and/or serious impairment on the quality of life and healthcare costs.
“This first release of data from the Medical Genome Reference Bank gives researchers a much more statistically powerful framework to identify new disease-causing gene variants,” says Thomas. “For instance, when we analysed genomes of prostate cancer patients, we found that using the MGRB as a ‘control’ gave us a 25% higher predictive power of disease-linked gene variants than another genome database that is commonly used by researchers to find such variants.”
The authors point out that over the next few years more data will be released from several large-scale WGS studies in rare diseases and cancer, such as the 100,000 Genomes Project, and population studies like the UK Biobank. “A synthesis of all forms of somatic and germline genomic variation is needed to inform our understanding of healthy ageing and disease susceptibility,” the study authors write. They propose that this study of healthy older Australians “constitutes a powerful and broadly applicable tool for genome-wide association studies of disease.”