Australian researchers led by the Garvan Institute of Medical Research in Sydney have compiled the first reference genome database of healthy older Australians, which potentially can predict disease-linked gene variants more accurately than has been previously possible.
Besides being the first reference genome database of healthy aged Australians, “this is the largest whole genome cohort of aged healthy individuals in the world to date,” said study leader David Thomas, professor, Garvan Cancer Research Theme Leader, and director of The Kinghorn Cancer Centre.
The researchers released the first 2,570 genomes of the Medical Genome Reference Bank (MGRB) and published their findings in the Jan. 23, 2020, edition of Nature Communications.
The MGRB is a collaboration led by Garvan, Monash University's ASPirin in Reducing Cardiovascular Events in the Elderly (ASPREE) study, and the Sax Institute's 45 and Up Study, a large ongoing study of healthy aging in Australia.
"A comprehensive analysis of healthy individuals can result in a much clearer understanding of which genes are or are not linked to disease,” said Thomas.
“The MGRB will provide an ideal background for the future of genomic research in Australia," he said. And while its 97% Caucasian European background continues the problem of lack of diversity in genomic sampling, he noted that its composition “reflects the demographic distribution in the aged Australian population.”
“This is a cohort of individuals who have survived past the age of 65 years, who have not developed the three major diseases affecting our community, namely cancer, cardiovascular disease [CVD] and dementia,” said Thomas.
“Although the MGRB can be used for the study of any genetic disease, including many types of cancer, it has been designed specifically for studies of cancer, CVD and dementia.”
Between any two unrelated individuals, there are literally millions of single genomic variations, some of which can cause disease, but the challenge is to identify exactly which variations those are.
The authors of the current study published the genomic data of 2,570 healthy Australians who were free from cancer, CVD or neurodegenerative disease until at least age 70, and who were also participants of the ASPREE and 45 and Up studies.
"This first release of data from the MGRB provides a statistically powerful framework to identify new disease-causing gene variants," said Thomas.
"For example, in a cohort of 80 prostate cancer patients in the 45 and Up study, as a control group, the MGRB was around 25% more powerful than the UK Biobank, which has a younger cohort, meaning we could achieve a statistically significant result with 25% fewer controls.”
Using whole genome sequencing, the researchers detected genetic changes associated with aging, including shorter telomeres, the regions of DNA near the ends of chromosomes, and less mitochondrial DNA.
“As cells age, their telomeres shorten with each cell division and we show that by sampling primarily white blood cells over a lifetime, we can observe shortening of telomeres with age,” said Thomas.
“Similarly, the number of mitochondrial genomes per blood cell reduces with age, perhaps due to their loss with each cell division,” Thomas told BioWorld.
Nevertheless, “we were able to detect changes in the genomes that could distinguish between healthy older individuals of the same age, but who have different physical function, suggesting that DNA in an individual's blood may provide a better indicator of their biological age than their chronological age.
"The ability to derive a measure of biological age may better predict health outcomes for individuals. As our population ages, understanding the genetic basis for healthy aging will become more and more important," said Thomas.
The first release of the data is freely available to researchers via the Vectis platform and, once completed, the MGRB will contain genomic data from more than 4,000 older Australians.
“These findings show that healthy aging may be associated with reductions in common genetic variants contributing to disease risk, i.e. the fewer the genetic risk factors you have, the more likely you are to live to an old age,” said Thomas. “While this seems intuitive, it has not been so strongly demonstrated previously.”
Twenty-eight of the individuals in the MGRB, or slightly more than 1%, had high-risk variants of genes known to affect disease risk.
Five individuals were genetically predisposed to hypercholesteremia through their variants in the APOB gene, while four had BRCA2 mutations, illustrating that “just because you carry these risk alleles, it does not mean you are guaranteed to develop the relevant disease – just that it is more likely,” he said. “It is possible to live to a ripe old age while carrying variants in genes we would ordinarily think confer a large risk for diseases like cancer.”
In addition to giving insights into health in the aged, the data can also be used to study disease in the young. “We are now using the MGRB to find the genetic causes of cancers, in particular sarcomas and cancers that arise in the young,” Thomas said. “These studies will also develop tools, which we will share with the research community, so they can use them to study their favorite diseases.”