Notes: In the CHS, ever smoking was defined as having smoked more than 100 cigarettes or five packs during the participant’s lifetime; hypertension was defined as a systolic blood pressure 140 mmHg or more or a diastolic blood pressure 90 mmHg or more or a history of hypertension and taking antihypertensive medication; diabetes was defined as fasting glucose more than 125 mg/dL or use of insulin or oral hypoglycemic medications. In Framingham Heart Study, ever smoking was defined as self-reported cigarette smoking of at least 1 cigarette/d for a year at any attended examination; total serum cholesterol was measured using an automated enzymatic procedure (44); hypertension was defined as blood pressure 140/90 mmHg or more or on antihypertensive medication; diabetes was defined as fasting blood glucose more than 125 mg/dL, a random blood glucose of more than 200 mg/dL, or use of insulin or oral hypoglycemic agents. In the Rotterdam Study, ever smoking was defined as self-reported ever smoking (cigarette, cigar, or pipe); hypertension was defined as systolic blood pressure 160 mmHg or more and/or diastolic blood pressure 100 mmHg or more and/or blood pressure–lowering medication with an indication for hypertension; total serum cholesterol was measured using an automated enzymatic procedure (40); diabetes was defined as self-reported diabetes at baseline. In the AGES-Reykjavik, ever smoking was defined as having smoked more than 100 cigarettes in one’s lifetime; total serum cholesterol was measured using an automated enzymatic procedure (40); hypertension was defined as systolic blood pressure 140 mmHg or more, diastolic blood pressure 90 mmHg or more, use of antihypertensive medications, or self-report; diabetes was defined as fasting glucose more than 125 mg/dL, use of insulin or oral hypoglycemic medications, or self-report. AGES-Reykjavik = Age, Gene/Environment Susceptibility-Reykjavik Study; CHS = Cardiovascular Health Study; CVD = cardiovascular disease.

of similar magnitude across the four cohorts (Figure 3; Supplementary Table 3).

19 supporting SNPs on chromosome 15 in or near the lon- gevity assurance homologue 3 (LASS3) gene, with the strongest association (OR = 0.79, p = 1.2 × 10−5) noted for rs8029244. The study-specific ORs for the 24 SNP associa- tions shown in Table 2 were in the same direction and were

Of the 24 strongest independent regions shown in Table 2, the 22 SNPs tested in all four CHARGE cohorts were selected for further evaluation, and 16 were successfully genotyped in the second stage cohorts. Only 1 of the 16 SNPs had a smaller p value after including the replication

Observed -log1 O(p-value)lambda=1.032   T2T T3 4Expected -log1 O(p-value) 

 78910 12 14 16 18 21Coordinate

Figure 2. Plot of genome-wide association study for longevity meta-analysis (persons surviving to age ≥90 years, n = 1,836, and comparison group, n = 1,955) showing the −log (p values) based on the fixed-effects meta-analysis by chro- 10 mosome. Line indicates threshold for genome-wide significance of 5 × 10−8.

Figure 1. Quantile–quantile plot for the 2,287,520 single-nucleotide poly- morphisms in the meta-analysis of survival to age 90 years or older.

egatS yrevocsiD dnoceS nedieL sulP EGRAHC–sisylana-ateM strohoC kramneD dnaselellA evitceffE )pb( ecnatsiD tceffE ydutS eziS elpmaS fo rebmuN tsesolC morF tsesolC noitceriD noitroporp( gnitroppuS tceffE ydutS ro eneG ecnerefeR eulaV pROkramneD/nedieL)latot fosPNSnoitceriDeulaV pROFAMrojaMroniMnoitcnuFeneGnoitisoPemosomorhCemaN rekraMrebmuN 860.38.0++534,201−−−−6−01 × 540.01.1−−46.042++++6−01 × ——†88.055−−−−6−01 × 290.59.0++29.076−−−−6−01 × ——†29.02++++6−01 × 300.98.0−+19.003−−−−5−01 × ——‡99.09+?+?5−01 × 200.09.0−+73.0801−−−−5−01 × 140.29.0++68.018−−−−5−01 × 100.21.1+−38.032++++5−01 × 971.29.0++39.004−−−−5−01 × 510.21.1+−09.062++++5−01 × ——‡98.00?+++5−01 × ——†46.086−+++5−01 × 7−01 × 77.628.0−−39.055−−−−5−01 × 200.09.0−+68.035−−−−5−01 × 440.39.0++58.018−−−−5−01 × ——†39.049−−−−5−01 × ——†39.049−−−−5−01 × 200.08.0+−49.064−−−−5−01 × ——†56.02++++5−01 × 410.68.0−+97.038−−−−5−01 × 600.90.1+−19.055++++5−01 × 890.01.1−+99.00++++5−01 × :sPNS gnitroppus fo rebmuN .elella ronim lanoitidda hcae rof era sRO .63 dliuB IBCN rof si noitisoP .sriap esab ni nevig era seneg ot secnatsiD .sisylana-atem dethgiew–ecnairav esrevni eht rof era seulaV p :setoN detneserp si noitamrofni cfiiceps-yduts ,noitcerid dna detupmi roF .50. < p noitaicossa evah dna )01. ≥ 2r( 22 esaeler UEC paMpaH eht ni PNS pot eht htiw DL ni era taht PNS pot eht fo bk 005 nihtiw sPNS fo rebmun sesaerced elella ronim = − ;09 naht erom lavivrus fo sddo sesaercni elella ronim = + :noitceriD .kramneD dna ,nedieL ,SHC ,SHF ,ydutS madrettoR ,ydutS kivajkyeR-ytilibitpecsuS tnemnorivnE/eneG ,egA :redro eht ;ydutS htlaeH ralucsavoidraC = SHC ;ygoloimedipE cimoneG ni hcraeseR gnigA dna traeH rof strohoC = EGRAHC ;yrtsecnA naeporuE niamuH emsihpromyloP ud edutE’d ertneC = UEC .detset ton = ? ;lavivrus fo

08–55 egA ot lavivruS htiW derapmoC )638,1 = n( redlO ro sraeY 09 egA ot lavivruS rof strohoC ruoF fo sisylana-ateM rof eulaV p yb deknaR snoitaicossA PNS 42 poT .2 elbaT stluseR sisylana-ateM egatS yrevocsiD dnoceS dna *)559,1

Study ORAGES 0.88Rotterdam 0.85FHS 0.85CHS 0.62Danish 0.92Leiden 0.76Combined 0.8 1 1.25Odds Ratio

(OR =

, p = .

). Findings for the other SNPs were in- consistent in direction of association such that the meta- analysis p values increased with inclusion of the second stage cohorts (Supplementary Table

). Pathway analysis did not reveal significant findings in the top associations, though some groupings were biologically plausible.

(OR = 0.92, p = .19). Findings for the other SNPs were in- consistent in direction of association such that the meta- analysis p values increased with inclusion of the second stage cohorts (Supplementary Table 3). Pathway analysis did not reveal significant findings in the top associations, though some groupings were biologically plausible.