Overlap between the associations of time to death and time to eventa

Top SNPs from time to death (time to event) analysis associated with different p- values in time to event (time to death) analysis

Top hit SNP Chr Closest reference Time to death Time to event Top SNPs from time to death (time to event) analysis associated with different p- gene values in time to event (time to death) analysis p Effect p Effect Total p   0.05 p  0.05 p   0.01 p  0.001 p  0.0001 Time to death 1 rs1425609 3 OTOL1 1.46E-06  0.005704  1119 693 235 132 37 22 2 rs766903 12 BIN2 1.61E-06  0.01315  37 27 4 5 0 1 3 rs12042640 1 ATG4C 1.71E-06  0.03701  93 60 19 4 0 10 4 rs11582903 1 LMO4 3.94E-06  0.7336  133 91 8 12 21 1 5 rs10259086 7 ORC5L 5.16E-06  0.03266  239 154 56 21 4 4 6 rs2769255 1 KCNQ4 5.17E-06  0.01322  287 151 68 56 7 5 7 rs17291546 6 LOC340156 7.65E-06  0.01624  29 19 9 1 0 0 8 rs12606100 18 NETO1 8.72E-06  0.02853  23 16 5 2 0 0 9 rs1274214 11 GRAMD1B 8.87E-06  0.0567  101 39 28 17 17 0 Time to event 1 rs16852912 3 MECOM 0.00589  3.37E-06  169 67 49 49 2 2 2 rs8001976 13 SUCLA2 0.01473  3.43E-06  433 198 91 46 59 39 3 rs4764043 12 GRIN2B 0.0017  6.10E-06  45 42 2 1 0 0 4 rs10202497 2 COL6A3 0.00035  8.22E-06  135 83 27 12 9 4 5 rs2367725 1 ST3GAL3 0.0274   9.31E-06  459 317 56 37 31 18



p-values are for the inverse variance-weighted meta-analysis. Total represents the number of SNPs in time to death (time to event) analysis within 500 kilo base pair of SNPs from the time to event (time to death) analysis that are in LD with the top SNPs from the time to death (time to event) analysis in the HapMap CEU release 22 (r2 zeus| 0.10) and have association p-value  0.05. Key: Chr, chromosome; Effect, meta-analysis direction of effect; LD, linkage disequilibrium; SNP, single nucleotide polymorphism. a Only SNPs that were nominally significant (p y < ( 0.05) for both traits are shown.

Table 4

Results from the gene annotation analysis using PANTHER

Biological process H. sapiens Number of Number of  I+ p-value p-value (reference) genes observed genes expected unadjusted adjusted a Time to death: Biological process unclassified 11321 238 367.71  1.29E-20 4.00E-19 Developmental processes 2152 152 69.9  1.39E-19 4.32E-18 Neuronal activities 569 65 18.48  8.94E-18 2.77E-16 Signal transduction 3406 199 110.63  9.09E-17 2.82E-15 Neurogenesis 587 64 19.07  1.43E-16 2.84E-14 Ectoderm development 692 68 22.48  2.33E-15 3.38E-13 Cell adhesion 622 57 20.2  7.00E-12 2.17E-10 Time to event: Developmental processes 2152 115 57.46  1.02E-12 3.16E-11 Biological process unclassified 11321 214 302.27  2.93E-12 9.08E-11 Neuronal activities 569 47 15.19   2.28E-11 7.08E-10

Candidate genes (genes observed) were in the neighborhood of single nucleotide polymorphisms (SNPs) associated with p value   1  10-3. For time to death 862 candidate genes were identified; 826 could be matched to the Protein ANalysis THrough Evolutionary Relationships (PANTHER) gene list. For time to event 704 candidate genes were identified; 679 could be matched to the PANTHER gene list. Extended lists of PANTHER pathways, biological processes, and molecular functions are listed in the Supplementary Tables (S13, S14). a Bonferroni correction multiplying the single-test p-value by the number of independent tests to obtain an expected error rate.

Path Designer Networks 1.4 Merged 7 | = \ 

Fig. 2. Network describing neuronal activities related to time to death. Pathway analysis of genes (single nucleotide polymorphisms; SNPs) associated with time to death. Genes are represented as nodes; edges indicate known interactions (solid lines depict direct and hatched lines depict indirect interaction). Human gene functions are color-coded as follows: red   unknown, yellow y=t transmembrane receptor and G protein coupled receptor, magenta (pink-purple) eee ee group/complex/other, bright green   ion channel, hunter green (dark green) =] peptidase, navy blue   transcription regulator, light blue Ape  transporter, beige eee  enzyme, orange   kinase, light green   cytokine, light purple   phosphate, gray   translation regulator, olive green  ligand-dependent nuclear receptor.

physiological processes and diseases that act as intermediate factors on the pathway to death (de Magalhaes et al., 2010). Therefore, any common variation in genes associated with aging probably has a small effect.

protein, GRID2 (glutamate receptor, ionotropic, delta 2)—a relatively new member of the family of ionotropic gluta- mate receptors which are the predominant excitatory neu- rotransmitter receptors in the mammalian brain, and have a role in neuronal apoptotic death, and RIMS1 (regulating synaptic membrane exocytosis 1), which regulates synaptic vesicle exocytosis and may be part of the protein scaffold of the cell.

Second, the largely negative findings of this and other studies contrast with the intriguing animal studies of lon- gevity. Very large effects of single genes on lifespan have indeed been observed in laboratory animals, but humans often have several homologues of these genes which might significantly differ in function or compensate for mutated genes through redundant mechanisms (Kuningas et al., 2008). This could explain why our top findings did not include genes in these pathways found in animal models. Animal models also represent genetically homogenous pop- ulations and are exposed to controlled environmental influ- ences. The lack of replication of animal model findings in humans suggests that the use of knockout animals may not provide the optimal approach to understanding the variation in survival in humans as interactions with environmental factors may obscure the associations and prevent the iden- tification of loci in humans.