One imagines that genetic copy number variations between individuals will prove to be much like other small differences in DNA, in that there are many tiny contributions to longevity, and it is hard to find consistent results in different study populations.
Copy number variations (CNVs) are rare losses and gains in DNA sequences that have been importantly implicated in the pathogenesis of various neurodevelopmental and psychiatric diseases. As opposed to SNP genotypes which have revealed common variants conferring modest relative risk to the individual with the variant, CNVs are often rare variants not observed or extremely rare in a normal control population and conferring high relative risk. SNP arrays have vastly improved the detection of CNVs across the human genome, [but] it remains to be determined if there are certain gene classes or networks of genes that are pathogenic or disease-causing in general, and if there are other gene networks that may be protective in the same manner. One way of testing this is to compare CNV states and frequencies between pediatric and geriatric subjects and determine if certain CNVs are lost in the older age group (i.e. suggesting pathogenic impact with shortened lifespan), and if other CNVs are enriched and considered protective.
To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry. [Positive] findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group, while only one duplication was enriched in the geriatric cohort. Population stratification correction resulted in 5 deletions and 3 duplications remaining significant in the replication cohort.
Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing. We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.