susrevksiR SCIS+SCEN)slortnoc924,dlotsedlo954(SCIS)slortnoc8081,dlotsedlo778(SCENHPECselellatnereferPNSwoR )A(pgisseyaBRO)A(pgisseyaBRO)A(pgisseyaBRO 42.0/82.00200.0)54.1;70.1(52.152.0/82.02121.0)45.1;48.0(41.132.0/82.08400.0)35.1;70.1(82.1723.0GG/GAvAA02430901sr12BRADA 22.0/72.03000.0)95.1;51.1(43.152.0/92.00402.0)66.1;29.0(52.122.0/72.05100.0)46.1;31.1(53.1213.0GG/GAvAA7417001sr2 31.0/61.02200.0)95.1;90.1(23.151.0/02.04830.0)79.1;79.0(83.121.0/51.00050.0)45.1;69.0(22.151.0GG/GAvAA2655082sr3 01.0/21.01120.0)45.1;10.1(42.111.0/41.08790.0)69.1;78.0(13.101.0/21.01190.0)35.1;29.0(91.1421.0CC/CAvAA949488sr4 18.0/97.01830.0)20.1;27.0(68.097.0/67.07121.0)41.1;06.0(38.018.0/87.04091.0)21.1;57.0(19.077.0GGvGA/AA3355082sr5 31.0/51.03430.0)94.1;99.0(12.161.071.09962.0)26.1;87.0(21.121.0/41.03501.0)05.1;19.0(71.1790.0GG/GAvAA3567832sr6 86.0/47.07100.0)86.1;11.1(73.166.0/27.05930.0)97.1;79.0(13.196.0/57.09420.0)38.1;20.1(63.1996.0GG/GAvAA5355082sr7 84.0/35.08000.0)24.1;80.1(42.134.0/15.06510.0)67.1;30.1(63.194.0/45.05500.0)54.1;40.1(32.164.0GG/GAvAA3455082sr8 48.0/78.05100.0)76.1;21.1(63.158.0/78.03791.0)47.1;08.0(91.138.0/88.05100.0)77.1;11.1(24.1148.0GG/GAvAA0168983sr9 24.0/83.07410.0)89.0;57.0(68.094.0/34.08240.0)10.1;36.0(97.004.0/53.09010.0)79.0;07.0(18.0244.0GGvGA/AA4843351sr01 03.0/62.06800.0)69.0;17.0(38.072.0/62.09683.0)13.1;47.0(59.003.0/62.06900.0)89.0;76.0(18.0103.0GG/GAvAA2916762sr11 86.0/27.03700.0)04.1;40.1(02.156.0/66.04843.0)73.1;08.0(50.196.0/57.04000.0)66.1;51.1(73.196.0GG/GAvAA2597832sr21 12.0/71.00300.0)39.0;56.0(87.072.0/22.06280.0)01.1;95.0(08.091.0/41.05000.0)68.0;55.0(96.0691.0GGvGA/AA91049271sr31 26.0/56.04020.0)43.1;00.1(61.176.0/56.08132.0)91.1;86.0(09.026.0/56.05700.0)54.1;50.1(32.136.0GG/GAvAA7518873sr411BRADA 84.0/34.03500.0)69.0;27.0(38.064.0/94.09862.0)54.1;38.0(80.184.0/04.05201,)58.0;16.0(27.074.0GGvGA/AA347414sr51 10.0/500.07920.0)80.1;91.0(64.0610.0/110.03791.0)79.1;51.0(85.0900.0/300.06900.0)39.0;50.0(72.0900.0GG/GAvAA9088382sr61 99.0/599.06310.0)52.8;11.1(37.2489.0/199.08801.0)33.01;36.0(92.2099.0/799.06310.0)92.91;21.1(17.31GGvGA/AA0188382sr71 10.0/500.09030.0)40.1;81.0(84.0610.0/110.04391.0)89.1;51.0(85.0900.0/300.06110.0)39.0;50.0(82.0900.0GG/GAvAA6188382sr81 dnaSCENehtninoitaicossaehtfostluserehttroper7–5snmuloC.2elbatnisasPNSehtfosliatededivorp4–1snmuloC.)3.22q12(1BRADAenegehtnisPNSeviftsalehtdna)3.51p01(2BRADAenegehtnierasPNS31tsrifehT ehtstroper6snmuloc,stekcarbnihtiwlavretnielbiderc%59dnaoitarsddoehtfoetamitsenaiseyaBehtstroper5nmuloc,yllacificepS.sledomevissecerdnatnanimodfonoissergercitsigolnaiseyaBnodesabstcejbustnerefer nehw1#ROsisehtopyhllunehtfoytilibaborproiretsopehtsirebmunsihT.1,siROehtfoetamitseroiretsopehtnehw)1,RO(p-1dna1.siROehtfoetamitseroiretsopehtnehw)1.RO(p-1sadenifedsitahtecnacifingisseyaB foytilibaborproiretsopehtstroper7nmuloC.namhtlAybdesoporpeulav-pseyaBehtotralimissitidnasisehtopyhllunehttsniagaecnedivegnortsedivorpseulavllamsos)1,ROetamitseewnehw1$ROro(1.ROetamitseew sihtnitnacifingiseratahtsPNS4ehteradlobnidethgilhgihdnaSCISehtnisnoitacilperehttroper01–8snmuloC.)50.0,ecnacifingisseyaB(snoitaicossatnacifingisehteradlobnidethgilhgiH.slortnocdnasesacnielellaksireht tnetsisnocevah81lla,SCISehtnisPNS4ylnodnaSCENehtniecnacifingislacitsitatshcaersPNS51ylnohguohtlA.detagerggaeraseidutsowtehtmorfatadehtnehwsisylanaehtfostluserehttroper21–11snmuloC.sisylana .regnortssemocebmehtfo11foecnacifingisehtdnatnacifingisniamersPNSlla,detagerggaeraseidutsowtehtfoatadnehwdnastceffe



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Figure 1. Pattern of LD among the SNP in ADARB1(chromosome 21) that are associated with exceptional longevity. The four plots display the pattern of LD captured by the SNPs associated with exceptional longevity in ADARB1 (chromosome 21) using data from the NECS, SICS, AJCS and JCS. The intensity of red represents the strength of LD measured by D9. doi:10.1371/journal.pone.0008210.g001

exhibit consistent associations in terms of odds ratios and allele frequencies and combining data from the NECS and SICS made these ten associations even stronger plus an additional three other SNPs became statistically significant. These SNPs tag a region of approximately 160Kb in ADARB2 that includes two blocks of LD (Figure 4).

associated variants in this gene that may not be captured by our SNP selection in the Japanese population.

Association of ADARB2 with Exceptional Longevity

We examined the associations of 114 SNPs in ADARB2 in the NECS and SICS samples using the same recessive and dominant models. Ten SNPs were strongly associated with extreme old age in the NECS, and one remains significant even after correcting for multiple comparisons (SNPs rs2387952, Bayesian significance 0.0004,0.05/145). Four of these significant SNPs (rs2805562; rs2805533; rs2805543; and rs1533484) were also replicated in the SICS (Bayes significance ,0.05) (Table 3). The remaining six SNPs did not reach statistical significance in the SICS but did

Tables 4 and 5 summarize the results of the replication of 10 of these SNPs in AJCS subjects. Two of the SNPs reach statistical significance in this set (rows 3 and 13) but one has opposite effects compared to the NECS and SICS (rows 13). However, SNPs in rows 1, 5–9, 11 and 12 have effects that are consistent with the NECS and SICS and, when the data of the 3 studies are aggregated, they become significant (columns 12–14). The SNPs in

1$2838809 1$2838810 1$2838816—  Normalized R 

Figure 2. Result of genotype cluster algorithm from BeadStudio. The three plots show the normalized intensities in polar coordinate and the cluster definition from BeadStudio for NECS subjects. The clear separation suggests that the genotype calls are robust. doi:10.1371/journal.pone.0008210.g002