POOL-SEQ Study of Bulgarian Centenarians Highlights the Relevance for Human Longevity of Gene Expression Pathways

In human longevity studies a large number of genetic variants with small effects have been identified, but these are not easily replicable in different populations. We have performed whole-exome sequencing of two DNA pools from: 32 Bulgarian centenarians and 61 young healthy controls, respectively. A total of 59935 filtered variants were discovered, 216 of which were included in Longevity Map database which lists 2843 longevity associated variants. Using Fisher’s exact test, 22 of these variants showed significantly higher allele frequency in the centenarian compared to the control pool and are thus positively associated with longevity. Other 24 variants had significantly higher frequency in the controls and could be considered as negatively associated with longevity. The risk C allele in rs429358 of the APOE gene was only detected in the control pool and with lower frequency compared to other populations. REACTOME analyses showed that over-represented pathways with positive longevity variants belong to expression/transcription network with leading role of TP53, interplaying with other genes (ATR, FANCD2, BAX, BRIP1), whereas those with negative longevity variants belong to the signal transduction network. Our results confirm the importance of studying centenarians in different populations to discover those combinations of variants that associate with longer health span.