@PhdThesis{diss_mods_00015782, author = {Badarinarayan, Nandini}, title = {Next-generation sequencing of centenarians to identify genetic variants predisposing to human longevity}, year = {2014}, publisher = {Christian-Albrechts-Universit{\"a}t zu Kiel}, address = {Kiel}, keywords = {Next-generation sequencing; human longevity; genetic variants; Next-Generation-Sequencing; Langlebigkeit beim Menschen; genetische Varianten}, abstract = {The genetic contribution to adult human lifespan is {\~}25-30{\%} and is assumed to be determined by rare variants or common variants with rather small effects. The current hypothesis is that long-lived individuals (LLI) are enriched with longevity-associated variants that may compensate for the damaging effects of disease-associated variants and are thought to be of rather low frequency. In this project, we combined next-generation sequencing with case-control association studies to identify new exonic longevity influencing variants as those are more likely to be functionally relevant due to amino acid substitution. To reach this goal, we performed whole genome and exome sequencing of six centenarians (108-114 years) of European origin using two different technologies (SOLiD and Illumina). A fraction of the detected single nucleotide variants (SNVs) were selected for a follow-up by genotyping based on two different approaches. The first approach focused on SNVs with minor allele frequencies (MAF) 1 to 50{\%}, which resulted in 116 SNVs that were genotyped in our German sample of 1,610 LLI and 1,104 controls. Seven significant association signals were obtained and further investigated for a replication experiment in independent French (1,269 LLI and 1,834 younger controls) and Danish populations (910 LLI and 760 controls), but none of the associations could be confirmed. The second approach was an intensive follow-up by focusing on low-frequency variants (MAF≤10{\%}). Using eight different bioinformatic prediction tools to evaluate the functional impact of SNVs and overlaying the initial SNV list with locations associated with genome-wide association (GWAS) hit regions resulted in 48 variants that were selected for genotyping, where three SNVs showed a significant association signal in the German longevity sample. The top-ranking SNV (PCCA=3.7e-08, OR=1.7) was selected for a replication experiment in the Danish population but could not be confirmed. In addition, longevity genes and pathways from known model organisms were used as filter masks for the variant selection.}, url = {https://macau.uni-kiel.de/receive/diss_mods_00015782}, file = {:https://macau.uni-kiel.de/servlets/MCRFileNodeServlet/dissertation_derivate_00005728/Diss_nbadarinarayan_Oct2014_PhDthesis.pdf:PDF}, language = {en} }