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Genomes of Healthy Elderly Show Fewer Disease-Linked Variants

NEW YORK – Researchers in Australia have constructed a genomic reference database of healthy older people, which could help scientists uncover the genetics of healthy aging.

The Medical Genome Reference Bank effort, launched in 2012, is to eventually include whole-genome sequencing data on more than 4,000 elderly individuals who don't have common aging-related conditions like cancer, dementia, or heart disease. Previous studies of the so-called 'Wellderly' have focused on identifying potentially protective genetic variants, finding some that might prevent cognitive decline. But researchers from the Garvan Institute of Medical Research, which is leading the new initiative, said having a baseline of healthy aging could help shed light on genetic variants that cause disease. 

The Garvan-led team published the first data release from their effort — sequencing and phenotyping data on 2,570 elderly Australians — this week in Nature Communications. As expected, this cohort had lower levels of common and rare variants linked to disease, though a small percentage still harbored known pathogenic variants.

"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," Garvan's David Thomas said in a statement. "The Medical Genome Reference Bank will provide an ideal background for the future of genomic research in Australia."

To build the Medical Genome Reference Bank, the researchers amassed data on more than 4,000 people from the Aspirin in Reducing Events in the Elderly (ASPREE) study and the 45 and Up Study from the Sax Institute who have lived to at least 70 years without developing cancer, cardiovascular disease, or dementia. They sequenced blood samples from 2,926 of these individuals, 2,570 of which passed quality control checks.

A small portion of these healthy elderly, about 1.1 percent, harbored pathogenic or likely pathogenic variants that the American College of Medical Genetics and Genomics recommends reporting clinically. However, those individuals with BRCA2, MSH2, or PMS2 mutations did not have personal histories of breast or colorectal cancer and those with DSG2, KCNH2, and SCN5A mutations did not have histories of cardiac arrest or stroke.

The portion of individuals with pathogenic variants in the MGRB cohort was still lower than in other cohorts. For instance, only two out of 717 MGRB participants originating from the 45 and Up Study had pathogenic alleles in tumor suppressor genes, but 12 out of 269 cancer cases in the same study had such mutations.

In general, compared to the gnomAD and UK Biobank cohorts, the new MGRB dataset was depleted of alleles associated with cancer, cardiovascular disease, and neurodegenerative diseases. Additionally, using polygenic risk scores for a range of phenotypes, the researchers found the MGRB cohort had lower scores than the others.

Still, 7.2 percent of the MGRB cohort showed clonal hematopoiesis of indeterminate potential, which is estimated to occur in about 10 percent of people over the age of 65. Telomere shortening, somatic Y chromosome loss, decreased mitochondrial copy number, and increased mitochondrial heteroplasmy — all signs of aging — were still present among the MGRB cohort. Additionally, grip strength and gait speed — also markers of aging — decreased with age in the cohort. 

As the cohort appears to reflect a healthy aging population, it could be used to uncover genetic variation that is unrelated to disease, the researchers said. When they used the MGRB cohort as a control when analyzing a set of prostate cancer patients, for example, that approach boosted their power to detect risk variants.

"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," Thomas said.