Table 1: Aging and Longevity Phenotypes for Framingham Heart Study 100K Project

Exam cycle(s) Phenotype Subgroup Number of Traits N (MV**) Offspring / Original Adjustment • Trait (variable name on the Cohort website*) Survival Traits: Cox regression Survival 2 1345 (1166) Cohort & Offspring Cox regression • Age at death (1. deathageX, 2. pooled Sex-specific deathageMV) 1. birth cohort 2. multivariable adjusted for birth cohort, education, smoking, obesity (BMI ≥ 30), CVD risk factors, co-morbidity measured at exam 1 Categorical traits: Logistic regression • Survival past the ALE (1. 2 1345 (1166) Cohort & Offspring Logistic regression deathpastALEX, 2. deathpastALEMV) pooled Sex-specific 1. birth cohort 2. multivariable adjusted for birth cohort, education, smoking, obesity (BMI ≥ 30), CVD risk factors, co-morbidity measured at exam 1 Morbidity-free survival (free of 2 558 (558) Cohort & Offspring Logistic regression CVD, cancer and dementia) pooled, exams closest to Sex-specific • At age 65 years (1. age 65 years 1. birth cohort morbidityfree65X, 2. 2. multivariable adjusted for birth cohort, education, morbidityfree65MVX) smoking, obesity, CVD risk factors measured at exam closest to age 65 years (within a 5 year horizon) Quantitative Traits: Linear regression Reproductive Aging 2 438 (378) Cohort & Offspring Linear regression • Age at natural menopause (1. pooled, women only 1. crude menoageX, 2. menoageMVX) 2. multivariable adjusted for smoking, BMI, parity, generation (measured at exams prior to menopause) Cognitive function 2 593 (462) Cohort & Offspring Linear regression • MMSE at age 65 years (1. MMSE65X, pooled, exams at age 65 Sex-specific 2. MMSE65MVX) 1. birth cohort • MMSE at the specified Offspring 2. multivariable adjusted for birth cohort, education, FSRP exam (1. MMSE5X, 2. MMSE5MVX, 1. measured at exam closest to age 65 years (5 year horizon) MMSE7X, 2. MMSE7MV, 1. MMSE5to7X, 2. MMSE5to7MVX) 6 1038 (913) Exam 5 Linear regression Exam 7 Sex-specific Exam 5 & 7 1. birth cohort average score 2. multivariable adjusted for birth cohort, education, FSRP; covariates measured at the specified exam Physical Performance 6 764 Exam 7 Linear regression • Hand grip (2. handgrip7x, 2. Exam 7 and Exam 27 Sex-specific‡ handgrips727x) 1. age • Walking speed (2. walkingspeed7x, 2. 2. multivariable adjusted for age, height, weight at the walkingspeed727x) specified exam Biologic Age by Osseographic 3 714 Offspring and Cohort Linear regression Scoring System (1. deltaOSSr, delta pooled Sex- and cohort-specific ranked residuals§ OSSrf, deltaOSSrm) exam 6/7 and exam 22 1. multivariable adjusted for age, height, BMI, menopause, estrogen use

Residuals from these models were used as traits to test for association with SNP genotypes. * The number preceding the variable name refers to the covariate adjustment in the last column of the table. The website with all results is found at http:// www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007; ** MV = N for multivariable trait ‡ cohort- and sex-specific residuals for traits that included both cohort and offspring; §cohort-specific for traits limited to one sex ALE = average life expectancy, BMI = body mass index, Co-morbidity = cardiovascular disease and cancer, CVD = cardiovascular disease, FSRP = profile, MMSE = mini-mental state exam, Risk factors = hypertension, diabetes, elevated cholesterol

on the 100K Affymetrix GeneChip. There were 2036 SNPs in the LGV1 region on chromosome 4 previously linked to exceptional longevity [11]. Table 4 shows the candidate genes with SNPs associated with an FBAT or GEE p-value < 0.01 for age at death including: FOXO1a, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN and for morbidity- free survival at 65 years including:GHR, LEPR, MORF4L1, PON1, PTH, and WRN. Biologic age by OSS shared 2 SNPs

Discussion

To our knowledge, this is the first dense GWAS of longev- ity and aging traits in a community-based sample of adults from two generations of the same families. Over 1300 men and women have detailed longevity and aging-

Table 2: Aging and Longevity Phenotypes† for FHS 100K Project: Results of Association and Linkage Analyses

2a. GEE, Top 5 p-values by Phenotype*

Trait SNP Chromosome Physical location GEE p-value FBAT p-value Gene Region (within 60 kb) Age at death rs1528753 11 90,523,987 8.1 × 10-8 0.024 rs2371208 7 81,982,510 2.6 × 10-6 0.031 rs10496799 2 139,261,401 1.4 × 10-5 0.735 NXPH2 rs10489006 4 31,444,987 3.6 × 10-5 0.078 rs3757354 6 16,235,386 6.4 × 10-5 0.316 MYLIP Morbidity-free survival at age 65 rs1412337 1 165,350,299 1.8 × 10-9 0.505 DPT rs32566 5 5,845,507 1.9 × 10-9 0.323 rs10484246 6 9,559,183 8.4 × 10-8 0.928 rs4831837 8 12,756,234 4.7 × 10-7 0.182 rs2639889 16 59,680,648 9.4 × 10-7 0.903 Age at natural menopause‡ rs10496265 2 81,580,466 1.1 × 10-8 0.001 rs10496262* 2 81,662,782 3.3 × 10-7 0.005 rs958672 2 154,896,075 1.9 × 10-6 0.087 GALNT13 rs291353 1 232,046,939 5.5 × 10-6 0.035 GNG4 rs726336 5 163,911,906 1.1 × 10-5 0.125 Walking speed exam 7 rs7137869 12 118,452,366 6.3 × 10-7 0.009 CCDC60 rs7662116 4 154,375,569 1.9 × 10-5 0.016 rs7972859* 12 118,452,765 2.5 × 10-5 0.005 CCDC60 rs9318312 13 74,489,506 5.8 × 10-5 0.266 rs1994854 4 78,124,824 9.4 × 10-5 0.280 rs7718104 5 122,183,258 1.2 × 10-4 0.011 SNX2 Biologic age by osseographic scoring system rs1463605 12 30,005,150 7.0 × 10-8 5.3 × 10-4 rs7176093 15 84,170,434 7.4 × 10-6 0.005 KLHL25 rs3772255 3 157,585,436 8.2 × 10-6 0.085 KCNAB1 rs726846 5 136,099,953 1.1 × 10-5 0.003 rs646983 13 29,413,553 1.2 × 10-5 0.003

2b. FBAT, Top 5 p-values by Phenotype*