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First Wellderly Findings Highlight Protective, Cognitive Variants

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NEW YORK (GenomeWeb) – Individuals who've managed to evade major disease into old age are more likely to carry genetic variants that may protect them against conditions such as Alzheimer's disease, heart disease, or cognitive decline, a new study suggests.

As part of the Wellderly study — an ongoing search for genetic factors contributing to a healthy lifespan — researchers from the Scripps Research Institute and elsewhere sequenced the genomes of 600 individuals who'd remained chronic disease- and serious medication-free until their 80th birthdays and beyond.

Results so far, published online today in Cell, revealed an over-representation of potentially protective rare and common variants the healthy agers — particularly variants suspected of diminishing Alzheimer's disease risk and warding of age-related declines in cognition.

"There was one theme that just kept coming back and that was the cognition story," co-senior author Eric Topol, director of the Scripps Translational Science Institute, told GenomeWeb. "Whether we look at the common [variant] side or the rare [variant] side."

"It wouldn't have been the [thing] we suspected for what makes the Wellderly tick," Topol added, though "a lot of things suggest that that's what distinguishes them."

Indeed, a closer look at the participant demographics revealed that they were not only better educated, on the whole, but also more frequent exercisers who might be making better lifestyle choices overall due to prolonged cognitive sharpness.

The Wellderly study has been in the works since around 2006. When the effort began, investigators planned to profile participant genomes primarily by array-based genotyping.

Since then, the project has mushroomed and migrated toward mainly genome sequence-based analyses. In 2011, Complete Genomics announced that it was partnering with Scripps researchers to generate whole-genome sequences for free for 1,000 healthy Wellderly participants over 80 years old.

For their current analysis, the researchers drew from data on 1,354 individuals between the ages of 80 and 105, including 600 individuals who had their whole genomes sequenced by Complete Genomics. Enrollment for the study "was actually very difficult," Topol said.

"We screened many, many thousands to find the ones who fulfilled the criteria," he explained, noting that "it's rare to find people at that age who have never had any chronic illness."

The Wellderly group is slightly enriched for individuals from Southern California, where a team of nurses helped screen elderly individuals to find those who fit the study's criteria. The researchers reached out to potential participants from across the US, Canada, and parts of Europe.

Though the group does include some centenarians, the team's focus was on finding individuals who remained free from chronic diseases such as Parkinson's, Alzheimer's, dementia, heart attack, autoimmune disease, blood clots, diabetes, cancer, stroke, and so on into old age, rather than encompassing anyone who was exceptionally long-lived.

That healthspan phenotype differs significantly from longevity alone, which is often studied in centenarians or super-centenarians who might have a wide range of different disease histories or status, Topol noted, and "the genomics turn out to be very different, too."

"[O]ur results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors," he and co-authors wrote.

For the current analysis, Complete Genomics sequenced 600 of the Wellderly participant genomes to average depths of around 56-fold coverage. The team compared that healthspan set to 1,507 age-unselected population controls from a preterm birth study by the Inova Translational Medicine Institute (ITMI), which was also sequenced on the Complete platform to 55-fold average coverage.

Cypher Genomics, a Scripps informatics spinout spearheaded by Topol and Nicholas Schork, the institute's bioinformatics and biostatistics director, performed clinical annotation of variants in the genomes.

The team's main analysis centered on 511 Wellderly participants and 686 ITMI population controls that passed quality control steps, ethnicity matching, and filtering for potential relatedness.

Consistent with unpublished findings from array-based studies of the Wellderly individuals, the researchers did not see dramatic differences when they compared common variants in the Wellderly participants and the population controls.

The healthy-aging elderly were a bit less likely to carry genetic variants implicated in coronary artery disease or Alzheimer's disease through past genome-wide association studies or GWAS meta-analyses, the team reported, including disease-associated alterations in the APOE-epsilon 4 gene.

But genomes from the healthy aging cohort did not show declines in risky variants associated with cancer, stroke, or type 2 diabetes — the other top causes of death in the US. And the Wellderly individuals seemed to have similar rates of rare pathogenic variants, prompting speculation that they may also carry protective alleles preventing diseases to manifest.

The study's authors also saw comparable allele frequencies of longevity-related variants in individuals from the Wellderly and control groups, prompting them to search for potentially protective variants.

In a genome-wide association search for common variants that might mitigate disease risk, for example, the team uncovered a handful of loci that were slightly, but not significantly, more common in the Wellderly cohort.

These included several major histocompatibility complex SNPs on chromosome 6, a locus implicated in cognitive performance and psychiatric disease risk, as well as a chromosome 2 site suspected of affecting cognitive decline risk and metabolism-related variants on chromosome 5.

Likewise, a look at rare variant associations uncovered nine very rare coding changes in a brain-expressed gene called COL25A1 that codes for a protein that can interact with the amyloid plaques that are believed to accompany Alzheimer's disease. Those variants, detected in 10 of the Wellderly participants, did not turn up in population controls.

On the lifestyle side, the Wellderly cohort had slightly higher-than-usual smoking rates, particularly amongst male participants who often had kicked the habit many years ago. They also tended to be more highly educated and exercised more frequently than individuals in the same age group from 2010 US census data.

Under the original agreement between Complete Genomics and the Wellderly team, the company planned to control access to the sequences. For example, Complete Genomics customers who signed up for Ingenuity Variant Analysis services in 2012 reportedly gained access to the database of control genomes used for the Wellderly study.

The Wellderly team has now terminated its agreement with Complete Genomics and does not anticipate having more than the current 600 genomes sequenced on that platform, Topol said. He noted that the genomes sequenced so far will be made available to the research community upon publication of today's Cell paper.

"We're hoping that that will help get others in the research community interested in the healthspan phenotype," he noted. "But more importantly for today, it will help be a reference genome for late onset diseases."

The team has now sequenced around 200 of the Wellderly genomes using Illumina instruments and Moleculo technology, in collaboration with Illumna's David Bentley. It plans to use Illumina technology to sequence the complete set of almost 1,400 genomes in the next year or so, if sufficient funding and/or partnerships can be secured.

To that end, Topol said he's interested in teaming up with groups at larger sequencing centers or elsewhere to crank through Illumina sequencing on the remaining 1,200 Wellderly genomes as quickly as possible.

The team is in the process of doing follow-up functional studies on induced pluripotent stem cells from some of the study participants. They have also been doing genome editing on some of these participant-derived cell lines for several years, first using zinc finger technology, followed by TALEN-based approaches, and, most recently, CRISPR-Cas9.

The researchers hope to see further replication and expansion of the current findings in much larger groups of healthy elderly individuals. 

"We know there are going to be a lot more protective alleles and modifier genes that are going to require large samples of such people," Topol said. "What we need now are much bigger numbers of healthspan individuals so we are guided as to what we're going to edit and do functional genomics on."

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