Burden of Common Complex Disease Variants in the Exomes of Two Healthy Centenarian Brothers

Abstract

Background: It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease. Objective: The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals. Methods: We compared the number of disease-associated alleles, and the proportion of alleles predicted to be functionally damaging, between the centenarian brothers and published population data. Mitochondrial sequence reads were extracted from the exome data in order to analyze mitochondrial variants. Results: The brothers carry a similar number of common disease-associated variants and predicted damaging variants compared to reference groups. They did not carry any high-penetrance clinically actionable variants. They carry mitochondrial haplogroup T, and one brother has a single heteroplasmic variant. Conclusion: Although our small sample size does not allow for definitive conclusions, a healthy aging and longevity phenotype is not necessarily due to a decreased burden of common disease-associated variants. Instead, it may be rare ‘positive' variants that play a role in this desirable phenotype.

Similar burden of pathogenic coding variants in exceptionally long‐lived individuals and individuals without exceptional longevity

“…A smaller study based on whole genome sequencing of 44 ELLI from our cohort identified 130 "Pathogenic/Likely Pathogenic" coding variants (Freudenberg-Hua et al, 2014 (Stevenson et al, 2015). These results are also consistent with another study that characterized the whole exome of a pair of ELLI brothers and did not find any significant difference between them and the population genome (Tindale et al, 2015). The consistency of our results with these studies steers away from the "perfect genome"…”

“…First-degree relatives of ELLI, including their offspring, demonstrate longer lifespan and decreased susceptibility to age-related diseases, such as cardiovascular disease, dementia, and cancer, compared to the general population (Atzmon et al, 2010;Balistreri et al, 2014;Barzilai, Gabriely, Gabriely, Iankowitz, & Sorkin, 2001;Gubbi et al, 2017;Sebastiani, Nussbaum, Andersen, Black, & Perls, 2015 (Broer et al, 2014;Deelen et al, 2011;Joshi et al, 2016;Pilling et al, 2016;Sebastiani et al, 2012). Several studies have noted that ELLI may carry pathogenic mutations that increase the risk for cancer or Alzheimer's disease (Freudenberg-Hua et al, 2014;Holstege et al, 2014;Stevenson et al, 2015;Tindale et al, 2015). These observations have led to the hypothesis that ELLI carry protective gene variants that "buffer" the effects of pathogenic variants (Bergman, Atzmon, Ye, MacCarthy, & Barzilai, 2007).…”

“…Although a few longevity‐associated genetic signatures and individual gene variants have been identified, fewer have been replicated (Broer et al, 2014; Deelen et al, 2011; Joshi et al, 2016; Pilling et al, 2016; Sebastiani et al, 2012). Several studies have noted that ELLI may carry pathogenic mutations that increase the risk for cancer or Alzheimer's disease (Freudenberg‐Hua et al, 2014; Holstege et al, 2014; Stevenson et al, 2015; Tindale et al, 2015). These observations have led to the hypothesis that ELLI carry protective gene variants that “buffer” the effects of pathogenic variants (Bergman, Atzmon, Ye, MacCarthy, & Barzilai, 2007).…”

“…Tindale et al, 2015), we identified many pathogenic variants among the ELLI. Further, our results also indicate that the ELLI carry a similar burden of pathogenic variation compared to control individuals from the same population without exceptional longevity.The similarity in amounts of variants was striking to us, especially given the expectation of somatic mutation accumulation previously reported(Milholland et al, 2015;Ye et al, 2013).…”

Allele-specific transcript abundance: A pilot study in healthy centenarians

“…Several studies have shown that long-lived individuals do not appear to carry a substantially lower number of common-complex disease risk alleles compared to typical individuals (1)(2)(3). It may be that despite carrying risk alleles, they express the diseaserelated variants at a lower level.…”