Abstract
Survival to extreme ages clusters within families. However, identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We study 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative genetic trait among survivors up to the top 10% of their birth cohort. We subsequently show a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.
Highlights
Survival to extreme ages clusters within families
Establishing a threshold that best isolates the genetic component of longevity and including mortality information of family members is important because the environmentally-related increase in lifespan over recent decennia has caused an increase in longevity phenocopies
We aim to establish the threshold for longevity in unselected multigenerational families and determine the importance of longevous family members for case selection so that those insights can be used in genetic studies to identify novel longevity loci
Summary
Survival to extreme ages clusters within families. identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. We aim to establish the threshold for longevity in unselected (for survival) multigenerational families and determine the importance of longevous family members for case selection so that those insights can be used in genetic studies to identify novel longevity loci. Zeeland was a region with difficult living conditions compared to Utah (see Methods section) In these datasets, we identify 20,360 three-generational families (F1–F3) containing index persons (IPs, F2), their parents (F1), siblings (F2), spouses (F2), and children (F3) comprising 314,819 persons in total. We examine the association between the survival, measured as age at death, of IPs (F2) and the number of parents (F1) and siblings (F2) belonging to the top 1–60% of their birth cohort, in a cumulative way (comparing mutually inclusive percentile groups). We explore potential environmental influences by studying spouses (F2) of longevous IPs (F2)
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