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Cardiovascular disease, cancer, and type 2 diabetes as young centenarians (Beekman et al., 2010), we expected to primarily find longevity-promoting alleles. However, although most of the 58 prioritized SNPs (n = 43) from the LLS GWAS showed a longevity-promoting effect ranging from 36 to 168%, none of them could be replicated in additional study populations of nonagenarian singletons. The only replicated locus is APOE, which is a mortality locus that has previously been reported to be the major locus responsible for Alzheimer's disease (Harold et al., 2009; Lambert et al., 2009; Seshadri et al., 2010), a well-known age-related disease. Nevertheless, none of the other Alzheimer's disease loci showed an association with survival to 90 years, which indicates that the remaining genetic variation in longevity in the LLS could not be explained by the genetic variation which contributes to Alzheimer's disease. In addition to APOE, we also observed evidence for association at the previously reported AKT1 locus (Pawlikowska et al., 2009) with survival into old age in the LLS GWAS, although the effect of this SNP is relatively small (25% decreased probability of becoming 90 years) compared to the effect of rs429358 (51%). The previously reported longevity-promoting effect of the FOXO3A locus could not be replicated in this study. This is probably due to the relatively low number of centenarians in the LLS GWAS case group, in which the effect of SNPs in FOXO3A on longevity seems to be most prominent. The still unexplained genetic variation in longevity might be attributable to rare variants or variants with small effects, which has previously been reported for other complex traits, such as Alzheimer's disease. These loci could not be identified in this study because of the relatively small number of cases in the LLS GWAS, the heterogeneity of factors influencing lifespan within populations, and the difference in the design of the studies used for replication. One way to identify variants with small effects would be to increase the initial sample size of the GWAS study and perform replication in other studies of nonagenarians. Given the higher heritability of longevity at older ages (Tan et al., 2004), one may also limit the study population. Between 1987 and 1989, 673 subjects aged 85 years and older were enrolled in a prospective study (Cohort 1). Between 1997 and 1999, 563 subjects were enrolled in the month of their 85th birthday with follow-up (Cohort 2). Subjects were visited at their home, and there were no exclusion criteria related to health. DNA was available from the combined cohorts consisting of 1208 subjects aged 85 years and older (Leiden 85-plus replication cases). Variants with small effects, rare variants with large effects might play a role in longevity. By whole-genome exome sequencing of long-lived subjects and their families, rare variants can be identified and associated with human longevity. In conclusion, we have shown that the deleterious effect of the ApoE e4 allele, tagged by rs2075650, is the single major hit in our GWAS study for longevity, indicating that no other major longevity locus was present among these nonagenarians. We confirmed the previously reported associations of the ApoE e4 allele with lipid metabolism parameters and report an additional effect on IGF-1 signaling in women. To identify genetic variants with smaller and protective effects on human lifespan, a meta-GWAS for longevity with ayears, 21% of the LLS siblings, 45% of the Leiden 85-plus participants, and 38% of the Danish 1905 cohort had died. Cox proportional hazards regression analysis was used to assess the association between rs2075650 and rs429358 and mortality, with adjustment for age and sex. The genotypes of rs2075650 and rs429358 were coded as 0 (homozygous for the common allele), 1 (heterozygous), or 2 (homozygous for the rare allele). Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were computed. A meta-analysis was performed by combining the results from the three studies using a fixed-effect model. P-values below 0.05 were considered statistically significant. All analyses were performed using R version 2.12.2 (http://www.r-project.org/).In the first sentence, "sup- ported" should be corrected to "supported". In the second sentence, "Lon-" should be corrected to "Longevity". In the third sentence, "NESDA" should not be split across two lines. In the fourth sentence, "STATASE" should be corrected to "Stata". In the fifth sentence, "Authors" should not be duplicated. In the sixth sentence, "Longevity" should not be split across two lines. In the seventh sentence, "GWAS" should not be split across two lines. 

In the eighth paragraph, there are several duplicated references that need to be removed. In addition, there is a typo in the reference for Cochran (1940), where "v  tests" should be corrected to "T tests". 

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