ArticlePDF Available

Replication of Genome-Wide Association Study Findings of Longevity in White, African American, and Hispanic Women: The Women's Health Initiative

Authors:

Abstract and Figures

Background No study has evaluated whether genetic factors are associated with longevity in African Americans or Hispanics, and it is unclear whether genetic factors are associated with healthy aging. Methods In this prospective study, we determined whether 14 genetic variants previously associated with longevity in genome-wide association studies were associated with survival to ages 85 and 90 in 11,053 postmenopausal white, African American, and Hispanic women from the Women’s Health Initiative. The associations of these variants with healthy aging, defined as survival to age 85 without chronic diseases or disability, were also determined. Results Among white women, three single nucleotide polymorphisms (SNPs) (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358 [APOE]) were significantly associated with survival to 90 years after correction for multiple testing (p < .001); rs4420638 and rs429358 were also significantly associated with healthy aging (p = .02). In African American women, no SNP was associated with longevity. In Hispanic women, 7 SNPs in linkage disequilibrium with a novel SNP, rs2149954, recently identified as being associated with increased longevity in a European population, were significantly associated with decreased survival to age 85 for carriers of the T versus C allele (p = .04). The association with decreased longevity was explained by higher risk of coronary heart disease in carriers of the T allele. There were no associations between FOXO3A SNPs and longevity in the analyses. In a meta-analysis, rs2075650 and rs429358 were significantly associated with longevity. Conclusions Future studies are needed to identify novel loci associated with longevity in African American and Hispanic women to determine biologic pathways regulating life span in these groups.
Content may be subject to copyright.
© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com. 1
Journals of Gerontology: Medical Sciences
cite as: J Gerontol A Biol Sci Med Sci, 2016, Vol. 00, No. 00, 1–6
doi:10.1093/gerona/glw198
Advance Access publication October 5, 2016
Research Article
Replication of Genome-Wide Association Study Findings
of Longevity in White, African American, and Hispanic
Women: The Women’s Health Initiative
Aladdin H. Shadyab,1 Charles Kooperberg,2 Alexander P. Reiner,3 Sonia Jain,4
JoAnn E.Manson,5,6 ChancellorHohensee,2 Caroline A.Macera,7 Richard A. Shaffer,7
Linda C.Gallo,8 and Andrea Z.LaCroix1
1Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego School of Medicine. 2Division
of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 3Department of Epidemiology, University of
Washington, Seattle. 4Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California,
San Diego School of Medicine. 5Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts. 6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 7Division of Epidemiology,
Graduate School of Public Health, San Diego State University, California. 8Department of Psychology, San Diego State University, California.
Address correspondence to Aladdin H.Shadyab, PhD, Division of Epidemiology, Department of Family Medicine and Public Health, University of
California, San Diego School of Medicine, 9500 Gilman Drive 0725, La Jolla, CA 92093. E-mail: ahshadya@ucsd.edu
Received May 10, 2016; Accepted September 18, 2016
Decision Editor: Stephen Kritchevsky, PhD
Abstract
Background: No study has evaluated whether genetic factors are associated with longevity in African Americans or Hispanics, and it is unclear
whether genetic factors are associated with healthy aging.
Methods: In this prospective study, we determined whether 14 genetic variants previously associated with longevity in genome-wide association
studies were associated with survival to ages 85 and 90 in 11,053 postmenopausal white, African American, and Hispanic women from the
Women’s Health Initiative. The associations of these variants with healthy aging, dened as survival to age 85 without chronic diseases or
disability, were also determined.
Results: Among white women, three single nucleotide polymorphisms (SNPs) (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358
[APOE]) were signicantly associated with survival to 90years after correction for multiple testing (p < .001); rs4420638 and rs429358 were
also signicantly associated with healthy aging (p= .02). In African American women, no SNP was associated with longevity. In Hispanic
women, 7 SNPs in linkage disequilibrium with a novel SNP, rs2149954, recently identied as being associated with increased longevity
in a European population, were signicantly associated with decreased survival to age 85 for carriers of the T versus C allele (p= .04).
The association with decreased longevity was explained by higher risk of coronary heart disease in carriers of the T allele. There were no
associations between FOXO3A SNPs and longevity in the analyses. In a meta-analysis, rs2075650 and rs429358 were signicantly associated
with longevity.
Conclusions: Future studies are needed to identify novel loci associated with longevity in African American and Hispanic women to determine
biologic pathways regulating life span in these groups.
Keywords: Gene—Aging—Successful aging—Minority
By 2060, it is expected that approximately 12 million women will be aged
85 and older, commonly referred to as the “oldest-old” age group (1).
Although attaining longevity is becoming increasingly common, healthy
aging, or reaching old age free of morbidity and disability, is more impor-
tant from a public health perspective. However, factors contributing to
longevity and healthy aging in women are not completely understood.
at University of California, San Diego on October 5, 2016http://biomedgerontology.oxfordjournals.org/Downloaded from
Heritability estimates for longevity range from 25% to 30%
(2). In previous candidate gene association studies, only variants
of apolipoprotein E (APOE) and forkhead box O3A (FOXO3A)
genes, which are involved in Alzheimer’s disease risk and insulin-
signaling pathways, respectively, have been consistently associated
with longevity (2–11). Although several longevity genome-wide
association studies (GWAS) and meta-analyses of GWAS have been
performed (12–16), only variants near the APOE locus have consist-
ently achieved genome-wide signicant associations with longevity
(13–16). However, prior GWAS were conducted among populations
of European descent, and no study has evaluated associations of
genetic variants with longevity in African Americans or Hispanics.
We determined whether genetic variants previously associated
with longevity in prior GWAS among European populations were
associated with survival to ages 85 and 90 and healthy aging in post-
menopausal white, African American, and Hispanic women from the
Women’s Health Initiative(WHI).
Methods
Study Population
The WHI is a large, prospective study investigating major deter-
minants of chronic diseases in 161,808 postmenopausal women
(17,18). Details of the study, including the use of existing genetic
data for this study and data collection, are discussed in greater detail
in the Supplementary Methods. All participants provided written
informed consent, and Institutional Review Board approval was
received by all participating institutions.
This study was exclusive to women with genetic data who were
born on or before August 29, 1929 and thus could survive to age
85 during follow-up ending August 29, 2014, representing up to
21 years of follow-up (Supplementary Figure1). All women were
from a similar birth cohort, minimizing bias due to varying lifetime
exposures. Only those whose survival status could be ascertained
were included. After quality control procedures, the nal sample size
consisted of 11,053 women (8,656 white, 1,858 African American,
and 539 Hispanic women).
SNP Selection
Single nucleotide polymorphisms (SNPs) signicantly associated with
longevity at the genome-wide level (p<5 × 10−8) in previous GWAS,
replication of GWAS ndings, and meta-analyses of GWAS pub-
lished through January 2015 were selected (5–7,10–16). All GWAS
were conducted in populations of European ancestry. The two SNPs
that dene the three isoforms of APOE and SNPs signicantly asso-
ciated with longevity in candidate gene studies for FOXO3A were
also selected; candidate gene studies were all conducted in European
populations except for one (11) that was conducted in Japanese
Americans. For candidate gene studies, SNPs were selected if statisti-
cally signicant after correction for multiple testing (eg, Bonferroni
correction). Henceforth, SNPs selected from previous studies will
be referred to as “index SNPs.” In total, 14 index SNPs were cho-
sen (5–7,10–16): rs2075650 (TOMM40); rs4420638 (APOC1);
rs7412 and rs429358 (APOE); rs2149954 (on chromosome 5);
and rs10457180, rs2764264, rs13217795, rs2802292, rs9400239,
rs3800231, rs479744, rs1935949, and rs4946935 (FOXO3A).
Individuals from different genetic ancestries exhibit divergent
linkage disequilibrium (LD) and allele frequency patterns. Index
SNPs associated with longevity in prior studies may thus not be in
LD with functional variants among African Americans or Hispanics,
and previous associations may be population specic. Therefore, for
African Americans and Hispanics, proxy SNPs in LD with the index
SNPs were chosen to fully explore replication of prior ndings in
these groups (see Supplementary Material).
Study Outcomes
Women were classied as having survived to age 85 or died before
age 85, and in a separate outcome, as having survived to age 90 or
died before age 90. The use of a dead comparison group from the
same birth cohort was important to be certain that these participants
never reached advanced old age. Death was conrmed by trained
physician adjudicators based on hospital records, autopsy or coro-
ner’s reports, or death certicates. Periodic linkage to the National
Death Index was performed for all participants, including those lost
to follow-up. Approximately 89% of women eligible for inclusion in
this study had complete survival status ascertainment.
Healthy aging was dened as survival to age 85years or older
without a history of major age-related diseases and with no impair-
ment of physical function or assistance in activities of daily living
(ADL). Physical function and ADL were assessed during study fol-
low-up using the RAND 36-item Health Survey (19). Good physi-
cal function for healthy aging was dened as not reporting any of
these limitations (20): limited at least “a little” on moderate activities
(moving a table, vacuuming, bowling, or golng; climbing one ight
of stairs; walking more than one mile; walking several blocks; or
bathing or dressing) or limited “a lot” on difcult performance items
(running, lifting heavy objects, or strenuous sports; lifting or carry-
ing groceries; climbing several ights of stairs; or bending, kneeling,
or stooping). Being able to perform all six ADL (feeding, dressing
and undressing, getting in and out of bed, taking a bath or shower,
doing own grocery shopping, and keeping track of and taking medi-
cines) without any help was also a criterion for healthy aging. This
resulted in three categories: healthy survivors, usual survivors, and
nonsurvivors.
Statistical Analysis
Comparisons of survivors and nonsurvivors on baseline characteris-
tics were performed using χ2 tests for categorical variables and two-
sample t tests or Wilcoxon’s rank-sum tests for normally distributed
and non-normally distributed continuous variables, respectively.
Comparisons of healthy aging categories were performed using χ2
tests for categorical variables and analysis of variance or Kruskal–
Wallis tests for continuous variables.
For all SNPs, count and reference alleles were dened. Separate
analyses were conducted in white, Hispanic, and African American
women. Logistic regression models assuming a log-additive genetic
effect were used to assess associations of SNPs with survival to age
85. For SNPs that were directly genotyped, SNP data were coded
as 0/1/2 (indicating the number of count alleles present), and for
imputed SNPs, the mean dosage of the count allele (a value between
0 and 2) was used. In the models, SNPs were used as continuous
variables. All models adjusted for the top ve principal components
to control for population stratication. Models also adjusted for
potential confounders including baseline age, WHI study compo-
nent, education, marital status, body mass index, physical activity,
alcohol consumption, smoking behavior, and history of age-related
diseases (see Supplementary Methods). Analyses were repeated with
survival to age 90 as the outcome in white and African American
women only, as a limited number of Hispanic women survived to
age 90. Multinomial logistic regression models were used to examine
2 Journals of Gerontology: MEDICAL SCIENCES, 2016, Vol. 00, No. 00
at University of California, San Diego on October 5, 2016http://biomedgerontology.oxfordjournals.org/Downloaded from
associations of SNPs with healthy aging in white women, using non-
survivors as the reference category. Similar variable inclusion criteria
as previously described were used. Healthy aging analyses were not
performed in African American or Hispanic women due to lower
sample sizes of aging categories in these groups. Because of varying
patterns of missing data in covariates, multivariable logistic regres-
sion models had lower sample sizes resulting from the complete case
analysis. Thus, models only adjusting for age and the rst ve prin-
cipal components were also t to make use of all of the available
genetic data. Results are reported as odds ratios and 95% condence
intervals. The odds ratios represent the change in the odds of lon-
gevity for each additional copy of the count allele. Atrans-ethnic
meta-analysis using a random-effects model was conducted to cal-
culate odds ratios combining white, African American, and Hispanic
women (see Supplementary Material for more detailed methods).
p Values were corrected for multiple testing using the Benjamini–
Hochberg procedure (21), which controls for the false discovery
rate and is a more powerful and less conservative approach than
Bonferroni correction. p Values were two tailed and considered
nominally statistically signicant at p less than .05 after correc-
tion. Analyses were conducted using Statistical Analysis Software
(SAS), Version 9.3 (SAS Institute, Cary, NC) and METASOFT for
the meta-analysis.
Results
Comparisons of survivors and nonsurvivors on baseline character-
istics are shown in the Supplementary Material and Supplementary
Tables 1–6. In white women, no index SNP was signicantly asso-
ciated with survival to age 85 after correction for multiple test-
ing (Supplementary Table7). However, in an analysis comparing
women who lived to age 90 with those who died before this age,
3 of 14 SNPs were replicated after correction for multiple testing
(Table1). The SNPs rs2075650 and rs4420638, which tag the lon-
gevity effects of APOE, were signicantly associated with survival
to age 90 (p < .001). Of the two SNPs that dene the three APOE
isoforms, only rs429358 was signicantly associated with survival to
age 90 (p < .001). To determine whether associations of rs2075650
and rs4420638 with survival to age 90 were independent of APOE,
models additionally adjusting for rs7412 and rs429358 were t.
After adjustment for these SNPs, rs2075650 and rs4420638 were
no longer signicantly associated with survival to age 90 (data
not shown). Other SNPs, including rs2149954 on chromosome 5,
and SNPs located at FOXO3A, failed to replicate in white women
(Supplementary Table 8). Findings were similar in models only
adjusting for age and population stratication, and rs7412 was
also signicantly associated with survival to age 90 in this analysis
(Supplementary Tables 9 and 10).
In African American women, no SNP was signicantly associated
with longevity (Supplementary Tables 11–13). In Hispanic women, no
SNP was signicantly associated with survival to age 85 after correc-
tion for multiple testing in the fully adjusted models (Supplementary
Table14); analyses for survival to age 90 were not performed due to
inadequate sample size. However, in models only adjusting for age
and population stratication, only seven SNPs in LD with rs2149954
were signicantly associated with survival to age 85 after correction
for multiple testing (p=.037; Table2 and Supplementary Table15).
Carriage of the T versus C allele was associated with decreased sur-
vival to age 85. To determine potential mechanisms that may explain
the link between these SNPs and longevity, associations with age-
related diseases, hypertension, and diastolic and systolic blood pres-
sures were evaluated (Supplementary Tables 16 and 17). There were
signicant associations between SNPs in LD with rs2149954 and
increased risk of coronary heart disease (p < .001) for carriers of the
T allele. Associations with other phenotypes were not observed.
Analyses for healthy aging were only performed in white women
due to small sample sizes of survival categories in the other ethnic
groups. Of the 14 SNPs, rs4420638 and rs429358 were signicantly
associated with healthy aging (Table3 and Supplementary Table18;
p=.021 and p=.021, respectively). After adjustment for rs7412 and
rs429358, rs4420638 was no longer signicantly associated with
healthy survival (data not shown). In analyses adjusting only for age
and population stratication, ndings were similar (Supplementary
Table19).
In a meta-analysis among white, African American, and Hispanic
women, rs2075650 (p= .04) and rs429358 (p=.04) were signi-
cantly associated with survival to age 85 (Supplementary Table20).
Furthermore, rs2149954 showed evidence of heterogeneity (I2=75;
p value for heterogeneity = .02). In a meta-analysis among white
and African American women, rs2075650 (p = .001), rs4420638
(p= .006), rs7412 (p=.02), and rs429358 (p < .001) were signi-
cantly associated with survival to age 90 (Supplementary Table21).
In sensitivity analyses, ndings were similar when comparing
women who survived to age 85 with those who died before age 80
Table1. Associations of Significant Loci From Previous Studies With Longevity in Postmenopausal White Women From the Women’s Health
Initiative
SNP Chromosome Position
Count Allele/Reference Allele
(count allele frequency)
OR (95% CI)
Uncorrected p Value Corrected p Value
Survived to 90 vs.
Died Before 90a
TOMM40b
rs2075650 19 45395619 G/A (0.13) 0.75 (0.63–0.87) <.001 <.001
APOC1b
rs4420638 19 45422946 G/A (0.16) 0.72 (0.61–0.85) <.001 <.001
APOEb
rs7412 19 45412079 T/C (0.08) 1.27 (1.04–1.54) .020 .069
rs429358 19 45411941 C/T (0.13) 0.68 (0.57–0.80) <.001 <.001
Notes: CI=condence interval; OR=odds ratio; SNP=single nucleotide polymorphism.
Bold p values are signicant at p < .05 after correction for multiple testing using the Benjamini-Hochberg procedure.
aMultivariable model adjusts for age, study membership, body mass index, physical activity, education, marital status, alcohol consumption, smoking behavior,
history of age-related diseases, and population stratication (N=3,380).
bGene.
Journals of Gerontology: MEDICAL SCIENCES, 2016, Vol. 00, No. 00 3
at University of California, San Diego on October 5, 2016http://biomedgerontology.oxfordjournals.org/Downloaded from
and women who survived to age 90 with those who died before age
80. Findings persisted after adjustment for genotyping source in the
models (data not shown).
Discussion
This was the rst study to determine whether genetic factors associated
with longevity in previous studies replicate in African American and
Hispanic women. No index SNP or SNP in LD with any index SNP was
signicantly associated with longevity in African American women. In
Hispanic women, SNPs in LD with a novel locus (rs2149954) identi-
ed as being associated with longevity in a recent meta-analysis of
GWAS of Europeans (14) were associated with survival to age 85.
Among white women, three SNPs were associated with survival to age
90: rs2075650, located at TOMM40; rs4420638, located at APOC1;
and rs429358, one of two SNPs dening the three APOE isoforms.
In a meta-analysis among all ethnic groups, rs2075650 and rs429358
were signicantly associated with survival to age85.
In previous GWAS among European populations, only genetic
variants near APOE have reached genome-wide signicance (13–16).
Among white women, we observed that rs2075650 and rs4420638 were
no longer signicantly associated with survival to age 90 after adjusting
for the two APOE SNPs, indicating that TOMM40 and APOC1 do not
have independent effects on exceptional survival but rather tag variation
at APOE (13). Index SNPs were not associated with survival to age 85 in
white women, supporting the observation that genetic factors may be of
greater importance at more advanced ages such as 90years and older (2).
In the current study, rs4420638 and rs429358 were signicantly
associated with healthy aging in white women. However, effect sizes
for healthy survival and usual survival were similar in magnitude,
suggesting that the association may be driven by survival to age 85
and not healthy aging per se. Limited genetic studies of healthy aging
have been conducted (2,22). Mechanisms allowing exceptional sur-
vivors to markedly delay or avoid disease and disability entirely are
currently unknown, but it is possible that genetic factors may play
a role. Aprevious study showed that nonagenarians carry the same
number of risk alleles for chronic diseases including cardiovascular
disease, type 2 diabetes, and cancer as younger controls, suggesting
that there may be genetic variants specically promoting longevity,
healthy aging, and a delay in disease (23).
Table3. Associations of SNPs With Healthy Aging in Postmenopausal White Women From the Women’s Health Initiative
SNP Chromosome Position
Count Allele/Reference
Allele (count allele
frequency)
OR (95% CI) OR (95% CI)
Uncorrected p
Value
Corrected p
Value
Healthy Survival
vs. Died Before
85a
Usual Survival
vs. Died Before
85a
TOMM40b
rs2075650 19 45395619 G/A (0.13) 0.83 (0.70–0.97) 0.84 (0.72–0.98) .027 .094
APOC1b
rs4420638 19 45422946 G/A (0.16) 0.78 (0.66–0.93) 0.80 (0.68–0.93) .003 .021
APOEb
rs7412 19 45412079 T/C (0.08) 1.16 (0.94–1.45) 1.15 (0.95–1.41) .236 .661
rs429358 19 45411941 C/T (0.13) 0.76 (0.64–0.90) 0.79 (0.68–0.93) .002 .021
Notes: CI=condence interval; OR=odds ratio; SNP=single nucleotide polymorphism.
Bold p values are signicant at p < .05 after correction for multiple testing using the Benjamini-Hochberg procedure.
aMultivariable model adjusts for age, study membership, body mass index, physical activity, education, marital status, alcohol consumption, smoking behavior,
and population stratication (N=4,517).
bGene.
Table2. Associations of SNPs With Longevity in Postmenopausal Hispanic Women From the Women’s Health Initiative
SNP Chromosome Position
Count allele/Reference allele
(count allele frequency)
OR (95% CI)
Uncorrected p Value Corrected p Value
Survived to 85 vs.
Died before 85a
rs2149954 5 157820602 T/C (0.31) 0.69 (0.52–0.93) .015 .053
rs7721599 5 157819991 T/C (0.31) 0.69 (0.52–0.93) .015 .053
rs7724836 5 157826281 A/G (0.35) 0.64 (0.48–0.85) .002 .037
rs4704775 5 157824556 A/G (0.27) 0.80 (0.59–1.08) .142 .368
rs7701003 5 157824481 G/A (0.33) 0.71 (0.53–0.95) .022 .070
rs13163917 5 157832300 G/A (0.35) 0.64 (0.48–0.85) .002 .037
rs17694395 5 157851580 T/C (0.35) 0.67 (0.50–0.90) .007 .037
rs9313775 5 157856776 A/G (0.35) 0.68 (0.51–0.91) .008 .037
rs10044792 5 157861839 T/C (0.35) 0.67 (0.50–0.90) .007 .037
rs10037337 5 157862392 G/T (0.35) 0.67 (0.50–0.90) .007 .037
rs12716344 5 157876908 G/C (0.36) 0.65 (0.49–0.88) .005 .037
Notes: CI=condence interval; OR=odds ratio; SNP=single nucleotide polymorphism.
Bold p values are signicant at p < .05 after correction for multiple testing using the Benjamini-Hochberg procedure.
aMultivariable model adjusts for age and population stratication (N=539).
4 Journals of Gerontology: MEDICAL SCIENCES, 2016, Vol. 00, No. 00
at University of California, San Diego on October 5, 2016http://biomedgerontology.oxfordjournals.org/Downloaded from
In the current study, variants at FOXO3A, which is involved
in the insulin/insulin-like growth factor 1 signaling pathway, were
not replicated in any ethnic group and were not signicant in the
meta-analyses. The association of FOXO3A with longevity has been
shown to be stronger in persons aged 95 and older and especially in
centenarians (6,11), which may partially explain the lack of associa-
tions between FOXO3A SNPs and longevity in ourstudy.
SNPs previously associated with longevity did not reach statis-
tical signicance among African American women, and the major-
ity did not reach signicance among Hispanic women. Lack of
signicance may be due to smaller sample size and lower power to
detect previous effect sizes compared with whites in these groups
(Supplementary Tables 22–24). Among whites, power was more than
99% for almost all SNPs. However, among African Americans, power
estimates ranged from 11.2% to 99.9% and were 80% or more for
TOMM40, APOC1, and some FOXO3A SNPs. Among Hispanics,
power was less than 80% for almost all SNPs. However, effect sizes
for SNPs among African Americans and Hispanics were similar to
those among white women and in the meta-analysis, rs2075650 and
rs429358 were signicantly associated with survival to age 85. These
ndings suggest that APOE may also be associated with longevity in
African American and Hispanic women. Although no study has eval-
uated genetic factors in relation to longevity in African Americans or
Hispanics, GWAS and replication studies of phenotypes such as type
2 diabetes, cancer, and obesity have revealed that there are ethnic
variations in SNP associations with various health outcomes (24–26).
They have also revealed novel loci associated with these phenotypes,
suggesting that there may also be other, unknown genes and mecha-
nisms that may inuence longevity in these populations.
In analyses only adjusting for age and population stratication,
several SNPs in LD with rs2149954, located on chromosome 5
downstream of EBF1 (11), were signicantly associated with lon-
gevity among Hispanic women. Furthermore, in the meta-analysis,
rs2149954 showed evidence of heterogeneity. Astudy in more than
12,000 European nonagenarians and younger controls observed
that carriage of the T allele at rs2149954 was signicantly associ-
ated with increased odds of longevity at the genome-wide level (14).
However, we observed that carriage of the T allele was associated
with decreased likelihood of longevity among Hispanic women. This
previous study also observed that the T allele at rs2149954 was
associated with lower cardiovascular mortality risk. However, our
ndings were explained by increased risk of coronary heart disease.
Collectively, these ndings support ethnic variations in the associa-
tion of rs2149954 with longevity.
This study has several limitations. There was lower power
to detect effect sizes reported in previous studies among African
Americans and Hispanics in our study due to smaller sample sizes in
these groups (Supplementary Tables 22–24). Women who enrolled
for additional follow-up were more likely to be white, educated, and
healthier at baseline than those who withdrew, thus our ndings may
be biased by selective attrition. It is possible that those who dropped
out were more likely to be cognitively impaired, which may have
biased APOE ndings.
Strengths of this study include a large, multiethnic sample of
women. This study was novel in that it was the rst to evaluate the
association of genetic factors with exceptional survival in African
American and Hispanic women. Additional strengths include the
prospective design with up to 21years of follow-up, high retention
of study participants over time, and adjudicated outcome ascertain-
ment. Finally, our population had a narrow age range, limiting birth
cohortbias.
Longevity is a complex phenotype that may be regulated by
multiple pathways (2). Recent studies are uncovering novel genes
that may be associated with longevity in different populations
(27,28). In our study, variation at APOE was signicantly associ-
ated with survival to age 90 among postmenopausal white women.
In Hispanic women, SNPs in LD with a novel SNP recently iden-
tied as being associated with longevity in Europeans were sig-
nicantly associated with decreased survival to age 85. Additional
studies will be important in identifying novel loci and biologic
pathways regulating life span in African American and Hispanic
women. In the future, when there are sufcient numbers of long-
lived ethnic minorities from different studies, data from multiple
cohorts should be combined to evaluate genetic factors associated
with longevity in these groups.
Supplementary Material
Please visit the article online at http://biomedgerontology.oxford-
journals.org/ to view supplementary material.
Funding
This work was supported by the National Heart, Lung, and Blood Institute,
National Institutes of Health, US Department of Health and Human
Services (contracts HHSN268201100046C, HHSN268201100001C,
HHSN268201100002C, HHSN268201100003C, HHSN268201100004C,
and HHSN271201100004C).
Acknowledgments
Role of the Sponsor: The National Heart, Lung, and Blood Institute has
representation on the WHI Steering Committee, which governed the design
and conduct of the study, the interpretation of the data, and preparation and
approval of manuscripts.
WHI Investigators:
Program Ofce: (National Heart, Lung, and Blood Institute, Bethesda,
Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan,
Leslie Ford, and Nancy Geller
Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center,
Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles
Kooperberg
Investigators and Academic Centers: (Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA) JoAnn E.Manson; (MedStar Health
Research Institute/Howard University, Washington, DC) Barbara V.Howard;
(Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick;
(The Ohio State University, Columbus, OH) Rebecca Jackson; (University of
Arizona, Tucson/Phoenix, AZ) Cynthia A.Thomson; (University at Buffalo,
Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/
Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport,
IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller;
(Wake Forest University School of Medicine, Winston-Salem, NC) Sally
Shumaker
Conflict of Interest
None declared.
References
1. US Census Bureau. 2014. National Population Projections: Summary
Tables. Table3. Projections of the Population by Sex and Selected Age
Groups for the United States: 2015 to 2060. https://www.census.gov/
population/projections/data/national/2014/summarytables.html. Accessed
October 8, 2015.
Journals of Gerontology: MEDICAL SCIENCES, 2016, Vol. 00, No. 00 5
at University of California, San Diego on October 5, 2016http://biomedgerontology.oxfordjournals.org/Downloaded from
2. Shadyab AH, LaCroix AZ. Genetic factors associated with longevity: a
review of recent ndings. Ageing Res Rev. 2015;19:1–7. doi:10.1016/j.
arr.2014.10.005
3. Garatachea N, Emanuele E, Calero M, etal. ApoE gene and exceptional longev-
ity: insights from three independent cohorts. Exp Gerontol. 2014;53:16–23.
doi:10.1016/j.exger.2014.02.004
4. Jacobsen R, Martinussen T, Christiansen L, et al. Increased effect of
the ApoE gene on survival at advanced age in healthy and long-lived
Danes: two nationwide cohort studies. Aging Cell. 2010;9:1004–1009.
doi:10.1111/j.1474-9726.2010.00626.x
5. Anselmi CV, Malovini A, Roncarati R, etal. Association of the FOXO3A
locus with extreme longevity in a Southern Italian centenarian study. Reju-
venation Res. 2009;12:95–104. doi:10.1089/rej.2008.0827
6. Flachsbart F, Caliebe A, Kleindorp R, etal. Association of FOXO3A vari-
ation with human longevity conrmed in German centenarians. Proc Natl
Acad Sci USA. 2009;106:2700–2705. doi:10.1073/pnas.0809594106
7. Pawlikowska L, Hu D, Huntsman S, etal. Association of common genetic
variation in the insulin/IGF1 signaling pathway with human longevity.
Aging Cell. 2009;8:460–472. doi:10.1111/j.1474-9726.2009.00493.x
8. Schächter F, Faure-Delanef L, Guénot F, etal. Genetic associations with
human longevity at the APOE and ACE loci. Nat Genet. 1994;6:29–32.
doi:10.1038/ng0194-29
9. Seripa D, Franceschi M, Matera MG, etal. Sex differences in the associa-
tion of apolipoprotein E and angiotensin-converting enzyme gene poly-
morphisms with healthy aging and longevity: a population-based study
from Southern Italy. J Gerontol ABiol Sci Med Sci. 2006;61:918–923.
10. Soerensen M, Dato S, Christensen K, etal. Replication of an association of
variation in the FOXO3A gene with human longevity using both case-con-
trol and longitudinal data. Aging Cell. 2010;9:1010–1017. doi:10.1111/
j.1474-9726.2010.00627.x
11. Willcox BJ, Donlon TA, He Q, etal. FOXO3A is strongly associated with
human longevity. Proc Natl Acad Sci USA. 2008;105:13987–13992.
doi:10.1073/pnas.0801030105
12. Broer L, Buchman AS, Deelen J, etal. GWAS of longevity in CHARGE
consortium conrms APOE and FOXO3 candidacy. J Gerontol ABiol Sci
Med Sci. 2015;70:110–118. doi:10.1093/gerona/glu166
13. Deelen J, Beekman M, Uh HW, et al. Genome-wide association study
identies a single major locus contributing to survival into old age; the
APOE locus revisited. Aging Cell. 2011;10:686–698. doi:10.1111/j.1474-
9726.2011.00705.x
14. Deelen J, Beekman M, Uh HW, etal. Genome-wide association meta-anal-
ysis of human longevity identies a novel locus conferring survival beyond
90years of age. Hum Mol Genet. 2014;23:4420–4432. doi:10.1093/hmg/
ddu139
15. Nebel A, Kleindorp R, Caliebe A, et al. A genome-wide association
study conrms APOE as the major gene inuencing survival in long-
lived individuals. Mech Ageing Dev. 2011;132: 324–330. doi:10.1016/j.
mad.2011.06.008
16. Sebastiani P, Solovieff N, Dewan AT, et al. Genetic signatures of excep-
tional longevity in humans. PLoS One. 2012;7:e29848. doi:10.1371/jour-
nal.pone.0029848
17. Anderson GL, Manson J, Wallace R, et al. Implementation of
the Women’s Health Initiative study design. Ann Epidemiol.
2003;13(suppl):S5–S17. doi:10.1016/S1047-2797(03)00043-7
18. The Women’s Health Initiative Study Group. Design of the Women’s
Health Initiative clinical trial and observational study. Control Clin Trials.
1998;19:61–109. doi:10.1016/S0197-2456(97)00078-0
19. Hays RD, Sherbourne CD, Mazel RM. The RAND 36-Item Health Survey
1.0. Health Econ. 1993;2:217–227. doi:10.1002/hec.4730020305
20. Sun Q, Townsend MK, Okereke OI, Franco OH, Hu FB, Grodstein F.
Adiposity and weight change in mid-life in relation to healthy survival
after age 70 in women: prospective cohort study. BMJ. 2009;339:b3796.
doi:10.1136/bmj.b3796
21. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical
and powerful approach to multiple testing. J R Statistic Soc. 1995;57:289–
300.
22. Minster RL, Sanders JL, Singh J, etal. Genome-wide association study and
linkage analysis of the healthy aging index. J Gerontol ABiol Med Sci.
2015;70:1003–1008. doi:10.1093/gerona/glv006
23. Beekman M, Nederstigt C, Suchiman HE, et al. Genome-wide associa-
tion (GWAS)-identied disease risk alleles do not compromise human
longevity. Proc Natl Acad Sci USA. 2010;107:18046–18049. doi:10.1073/
pnas.1003540107
24. Hoffmann TJ, Van Den Eeden SK, Sakoda LC, et al. A large multi-
ethnic genome-wide association study of prostate cancer identifies
novel risk variants and substantial ethnic differences. Cancer Discov.
2015;5:878–891. doi:10.1158/2159-8290.CD-15-0315
25. Ng MC, Shriner D, Chen BH, etal. Meta-analysis of genome-wide associa-
tion studies in African-Americans provides insights into the genetic archi-
tecture of type 2 diabetes. PLoS Genet. 2014;10:e1004517. doi:10.1371/
journal.pgen.1004517
26. Tan LJ, Zhu H, He H, etal. Replication of 6 obesity genes in a meta-
analysis of genome-wide association studies from diverse ancestries. PLoS
One. 2014;9:e961. doi:10.1371/journal.pone.0096149
27. Donlon TA, Morris BJ, He Q, etal. Association of polymorphisms in
connective tissue growth factor and epidermal growth factor receptor
genes with human longevity. J Gerontol A Biol Sci Med Sci. 2016, in
press. doi:10.1093/gerona/glw116
28. Crocco P, Montesanto A, Passarino G, Rose G. Polymorphisms falling
within putative miRNA target sites in the 3UTR region of SIRT2 and
DRD2 genes are correlated with human longevity. J Gerontol ABiol Sci
Med Sci. 2016;71:586–592. doi:10.1093/gerona/glv058
6 Journals of Gerontology: MEDICAL SCIENCES, 2016, Vol. 00, No. 00
at University of California, San Diego on October 5, 2016http://biomedgerontology.oxfordjournals.org/Downloaded from
... Parental longevity likely represents the combined effects of genetic, behavioral and environmental factors transmitted across generations that, throughout the life course, Parental longevity predicts healthy ageing among women influence ageing outcomes among offspring. The protective association between parental longevity and adverse health outcomes may be largely due to genetic factors [4,27,28]. In a recent genome-wide association study, 10 genetic loci were associated with attained parental age, including APOE, a gene associated with longevity [4,27,28]. ...
... The protective association between parental longevity and adverse health outcomes may be largely due to genetic factors [4,27,28]. In a recent genome-wide association study, 10 genetic loci were associated with attained parental age, including APOE, a gene associated with longevity [4,27,28]. In the WHI, single nucleotide polymorphisms representing variation in APOE were associated with longevity and a composite outcome of healthy ageing defined similarly to the one used in the present study [27]. ...
... In a recent genome-wide association study, 10 genetic loci were associated with attained parental age, including APOE, a gene associated with longevity [4,27,28]. In the WHI, single nucleotide polymorphisms representing variation in APOE were associated with longevity and a composite outcome of healthy ageing defined similarly to the one used in the present study [27]. Offspring may inherit genetic factors that protect against major diseases and disability; however, it is unknown whether a similar set of genetic factors influences both disease and disability. ...
Article
Objective: to examine the association of parental longevity with healthy survival to age 90 years. Methods: this was a prospective study among a racially and ethnically diverse cohort of 22,735 postmenopausal women from the Women's Health Initiative recruited from 1993 to 1998 and followed through 2017. Women reported maternal and paternal ages at death and current age of alive parents. Parental survival categories were <70, 70-79 (reference), 80-89 and ≥90 years (longevity). Healthy ageing was defined as reaching age 90 without major chronic conditions (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or physical limitations. Results: women whose mothers survived to ≥90 years were more likely to attain healthy ageing (OR, 1.25; 95% CI, 1.11-1.42) and less likely to die before age 90 (OR, 0.75; 95% CI, 0.68-0.83). Women whose fathers survived to ≥90 years did not have significantly increased odds of healthy ageing but showed 21% (OR, 0.79; 95% CI, 0.70-0.90) decreased odds of death before age 90. Women whose mother and father both lived to 90 had the strongest odds of healthy ageing (OR, 1.38; 95% CI, 1.09-1.75) and decreased odds of death (OR, 0.68; 95% CI, 0.54-0.85). The proportion of healthy survivors was highest among women whose mother and father lived to 90 (28.6%), followed by those whose mother only lived to 90 (23.2%). Conclusions: parental longevity predicted healthy ageing in a national cohort of postmenopausal women, supporting the view that genetic, environmental, and behavioral factors transmitted across generations may influence ageing outcomes among offspring.
... The first genetic association study of aging in racial and ethnic minority populations was based on the Women's Health Initiative (WHI) cohort, which took a candidate gene approach to evaluate variants associated with healthy aging and survival in postmenopausal African American, Hispanic, and White women (Shadyab et al., 2017). Fourteen single nucleotide polymorphisms (SNPs) from previous GWAS studies of longevity in primarily European populations were specifically evaluated to determine if these J o u r n a l P r e -p r o o f SNPs were also associated with longevity in postmenopausal women (Shadyab et al., 2017). ...
... The first genetic association study of aging in racial and ethnic minority populations was based on the Women's Health Initiative (WHI) cohort, which took a candidate gene approach to evaluate variants associated with healthy aging and survival in postmenopausal African American, Hispanic, and White women (Shadyab et al., 2017). Fourteen single nucleotide polymorphisms (SNPs) from previous GWAS studies of longevity in primarily European populations were specifically evaluated to determine if these J o u r n a l P r e -p r o o f SNPs were also associated with longevity in postmenopausal women (Shadyab et al., 2017). None of the selected SNPs were significantly associated with longevity in African American or Hispanic women in fully adjusted models, but when models were adjusted only for population stratification and age, 7 SNPs were significantly associated with survival to 85 years of age in Hispanic women (Shadyab et al., 2017). ...
... Fourteen single nucleotide polymorphisms (SNPs) from previous GWAS studies of longevity in primarily European populations were specifically evaluated to determine if these J o u r n a l P r e -p r o o f SNPs were also associated with longevity in postmenopausal women (Shadyab et al., 2017). None of the selected SNPs were significantly associated with longevity in African American or Hispanic women in fully adjusted models, but when models were adjusted only for population stratification and age, 7 SNPs were significantly associated with survival to 85 years of age in Hispanic women (Shadyab et al., 2017). These SNPs were in linkage disequilibrium with the rs2149954 variant, which was previously associated with longevity in a separate study of European ancestry. ...
Article
The pursuit to discover the fundamental biology and mechanisms of aging within the context of the physical and social environment is critical to designing interventions to prevent and treat its complex phenotypes. Aging research is critically linked to understanding health disparities because these inequities shape minority aging, which may proceed on a different trajectory than the overall population. Health disparities are characteristically seen in commonly occurring age-associated diseases such as cardiovascular and cerebrovascular disease as well as diabetes mellitus and cancer. The early appearance and increased severity of age-associated disease among African American and low socioeconomic status (SES) individuals suggests that the factors contributing to the emergence of health disparities may also induce a phenotype of ‘premature aging’ or ‘accelerated aging’ or ‘weathering’. In marginalized and low SES populations with high rates of early onset age-associated disease the interaction of biologic, psychosocial, socioeconomic and environmental factors may result in a phenotype of accelerated aging biologically similar to premature aging syndromes with increased susceptibility to oxidative stress, premature accumulation of oxidative DNA damage, defects in DNA repair and higher levels of biomarkers of oxidative stress and inflammation. Health disparities, therefore, may be the end product of this complex interaction in populations at high risk. This review will examine the factors that drive both health disparities and the accelerated aging phenotype that ultimately contributes to premature mortality.
... The comparison of results of genetic association studies of AD and human longevity showed that many highly significant genetic variants associated with AD are also associated with longevity traits (Lu et al., 2014;Yashin et al., 2018b;Shadyab et al., 2017). It is interesting to know whether SI_PRS indices constructed for AD are also associated with longevity traits. ...
Article
Emerging evidence from experimental and clinical research suggests that stress-related genes may play key roles in AD development. The fact that genome-wide association studies were not able to detect a contribution of such genes to AD indicates the possibility that these genes may influence AD non-linearly, through interactions of their products. In this paper, we selected two stress-related genes (GCN2/EIF2AK4 and APP) based on recent findings from experimental studies which suggest that the interplay between these genes might influence AD in humans. To test this hypothesis, we evaluated the effects of interactions between SNPs in these two genes on AD occurrence, using the Health and Retirement Study data on white indidividuals. We found several interacting SNP-pairs whose associations with AD remained statistically significant after correction for multiple testing. These findings emphasize the importance of nonlinear mechanisms of polygenic AD regulation that cannot be detected in traditional association studies. To estimate collective effects of multiple interacting SNP-pairs on AD, we constructed a new composite index, called Interaction Polygenic Risk Score, and showed that its association with AD is highly statistically significant. These results open a new avenue in the analyses of mechanisms of complex multigenic AD regulation.
... 9,10 Both SNVs are also associated with memory and cognitive function, cerebral spinal fluid biomarkers for immune response, 11 oxidative stress markers, 9 and longevity. [12][13][14] However, because both SNVs are in moderate LD (0.2 < r 2 < 0.8) with rs429358, these associations may not be independent of the ε4 allele. ...
Article
Importance The ε2 and ε4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 near the APOC1 gene, it is unknown whether these associations are independent of the ε2 and ε4 alleles. Objective To assess whether variants near APOE are associated with AD independently of the ε2/ε3/ε4 genotype. Design, Setting, and Participants In this genetic association study of the Alzheimer’s Disease Genetics Consortium imputed genotype at data, 14 415 variants near APOE (±500 kilobase) for 18 795 individuals with European ancestry were tested for association with AD using 4 logistic mixed models adjusting for sex, cohort, population structure, and relatedness. Model 1 had no APOE adjustment, and model 2 adjusted for the count of ε2 and ε4 alleles. Model 3 was restricted to ε3 homozygotes, and model 4 was restricted to ε4 homozygotes. Data were downloaded from May 31, 2018, to June 3, 2018, and analyzed from November 1, 2018, to June 24, 2020. Main Outcomes and Measures Alzheimer disease affectation status was defined by clinicians using standard National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria. Association was evaluated using Score tests; results with P < .05 divided by the number of independent tests per model were considered statistically significant. Results Among the 18 795 individuals in the study, 9704 were affected by AD and 9066 were control individuals; the median age at onset/evaluation was 76 (interquartile range, 70-82) years; and 11 167 were female (59.4%). Associations with AD were found for rs2075650 (odds ratio [OR], 2.59; 95% CI, 2.45-2.75; P = 3.19 × 10⁻²²⁸) and rs4420638 (OR, 2.77; 95% CI, 2.62-2.94; P = 2.99 × 10⁻²⁵⁴) without APOE adjustment. Although rs2075650 was nominally associated with AD among the ε4 homozygotes (OR, 1.33; 95% CI, 1.00-1.77; P = .047), the association between rs4420638 and AD was eliminated by APOE adjustment (model 2 OR, 1.06 [95% CI, 0.96-1.18; P = .24]; model 3 OR, 1.13 [95% CI, 0.95-1.34; P = .18]; model 4 OR, 0.90 [95% CI, 0.56-1.45; P = .66]). There was a significant association between rs192879175 and AD among ε3 homozygotes (OR, 0.50; 95% CI, 0.37-0.68; P = 8.30 × 10⁻⁶). Conclusions and Relevance The results of this genetic association study suggest that ε2/ε3/ε4 alleles are not the only variants in the APOE region that are associated with AD risk. Additional work with independent data is needed to replicate these results.
... With regard to longevity three SNPs (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358 [APOE]) were significantly associated with survival to 90 years after correction for multiple testing (p < .001) (Shadyab et al., 2017). A haplotype analysis suggested that individuals carrying the haplotype A-A-A-A-T-A-T-G-C-A (rs7254892-rs157580-rs2075649-rs2075650-rs157582-rs8106922-rs1160985-rs405697-rs439401-rs445925) tended to have longer lifespan than those carrying the most common haplotype G-G-A-A-C-A-C-A-T-G (OR = 1.59, 95% CI = 1.19-2.12, ...
Article
Full-text available
Background The APOE ‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE ‐ε4 are at variance. Methods We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V‐VI), respectively, and in 150 controls without major neurodegenerative diseases. Results We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE ‐E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE‐ E3 was identified as risk haplotype of high‐ (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40 , increased the risk of high‐, but not intermediate likelihood AD on the APOE ‐ε3/ε3 background (p = .0230). Conclusion The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.
... The report average age of the case was 97 years old (range from 90-110 years) and for the control was 59 years old (range from 18 -80 years). There were two extremity studies in which the case studies in the USA age is between 85-90 years [1] and the study in Danish age was range from 95-115 years old [29]. ...
Conference Paper
Full-text available
ABSTRAC The use of systems biology and bioinformatics to deal with the complexity inherent in aging research has played a major role. Genome-wide association studies (GWAS) is a means of detecting longevity-associated with genetic variants. The numbers of genetic variants found to associate with longevity and the most convincing human longevity genes today are APOE and FOXO3A which have frequently been associated with longevity. We conducted a systematic review to identify studies that contain the relevant data. Odds ratios (OR) and 95% confidence interval (CI) and P<0.05 for significant tests were used to figure out the genomic association between the genes and human longevity. There are a positive association of rs2802288 (OR = 1.08, 95% CI = 0.93-1.25, p = 0.03) and rs2764264 (OR = 1.25, 95% CI = 0.90-1.73, P = 0.01) between FOXO3A polymorphisms and human longevity on pooled analysis, specifically with male longevity but there is no association with rs13220810 polymorphism (OR = 0.96, 95% CI = 0.80-1.16, P = 0.31). Rs7412 polymorphism of APOE indicates a significant association which was more likely with human longevity (OR = 1.30, 95% CI = 0.50-2.83, P = 0.01) and rs429358 polymorphism of APOE was less likely to occurred for longevity with a negative significant association (OR = 0.50, 95% CI = 0.37-0.67, P = 0.01). It was confirmed that there are an association between FOXO3A and APOE with human longevity on polymorphisms. Further genotyping should be done to verify more potential markers or polymorphisms related to human longevity.
... Genetic variation in APOE is well known to be associated with longevity and lifespan, with the first report more than two decades ago in a small candidate gene study 27 . Since then, there have been numerous candidate gene studies, including individuals of diverse ancestry, which have identified associations of ApoE with longevity [28][29][30][31][32] . However, thus far, rs7412, the ApoE ε2-defining, genetic variant has not been reported to show a genome-wide significant association in GWA studies of longevity and lifespan. ...
Article
Full-text available
Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
... Network analysis suggested age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity [46]. Racial differences were apparent, there being no association of any SNP with longevity in African American women [47]. A meta-analysis of data from different racial groups found a non-significantly higher association of ε2/ε2 compared with ε3/ε3 genotype with longevity [48]. ...
Article
Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during aging profoundly affect cellular function and stress resistance. Dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. Large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. As the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive “leak”. There is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. Together, these phenomena contribute to aging.
... We replicated genome-wide significant associations with human longevity of SNPs in the APOE and TOMM40 genes found in earlier GWAS of human longevity that used different data. Specifically, we directly replicated: rs769449 in APOE (14,24); rs2075650 in TOMM40 (25,26); rs71352238 in TOMM40 (27). Using the HaploReg 4.1 tool (28), we also indirectly replicated SNP rs4420638 previously associated with longevity (29) as the rs56131196 SNP in a region of APOC1, identified in our study, is in high LD (r 2 = 1, D′ = 1) with the "longevity SNP" rs4420638. ...
Article
The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this paper, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.
Article
The clinical presentation and the pathological processes underlying Alzheimer's disease (AD) can be very heterogeneous in severity, location, and composition including the amount and distribution of AB deposition and spread of neurofibrillary tangles in different brain regions resulting in atypical clinical patterns and the existence of distinct AD variants. Heterogeneity in AD may be related to demographic factors (such as age, sex, educational and socioeconomic level) and genetic factors, which influence underlying pathology, the cognitive and behavioral phenotype, rate of progression, the occurrence of neuropsychiatric features, and the presence of comorbidities (e.g., vascular disease, neuroinflammation). Heterogeneity is also manifest in the individual resilience to the development of neuropathology (brain reserve) and the ability to compensate for its cognitive and functional impact (cognitive and functional reserve). The variability in specific cognitive profiles and types of functional impairment may be associated with different progression rates, and standard measures assessing progression may not be equivalent for individual cognitive and functional profiles. Other factors, which may govern the presence, rate, and type of progression of AD, include the individuals' general medical health, the presence of specific systemic conditions, and lifestyle factors, including physical exercise, cognitive and social stimulation, amount of leisure activities, environmental stressors, such as toxins and pollution, and the effects of medications used to treat medical and behavioral conditions. These factors that affect progression are important to consider while designing a clinical trial to ensure, as far as possible, well-balanced treatment and control groups.
Article
Full-text available
A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously-identified locus 6q25.3 that replicated in PEGASUS (N=7,539) and MEC (N=4,679) (p=1.0x10(-19), OR=1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (p=1.3x10(-23)) and SLC22A3 (p=3.2x10(-52)). At the known 19q13.33 locus rs2659124 (p=1.3x10(-13), OR=1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (p<1.0x10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic Whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained ~7.6% of disease heritability. The entire GWAS array explained ~33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (p=0.004). Copyright © 2015, American Association for Cancer Research.
Article
Full-text available
Many studies have suggested that individual differences in aging phenotypes may be associated to polymorphisms affecting gene regulation. As single-nucleotide polymorphisms (SNPs) in the 3′-untranslated regions (3′UTR) targeted by microRNAs (miRNAs) can alter the strength of miRNA binding (and, consequently, the regulation of target genes), we wondered whether these SNPs (known as miRSNPs) affect the individual chance to become long-lived. Thus, we estimated the effect of miRSNPs falling in the 3′-untranslated regions of 140 aging-related genes on the DNA/miRNA bond. The 24 miRSNPs with the highest difference of binding energy between the two alleles were then investigated for their association with longevity by case–control analysis. Two SNPs, SIRT2-rs45592833 G/T and DRD2-rs6276 A/G, provided a significant association with human longevity, also after correcting for multiple comparisons. For both SNPs, the minor allele was associated with a significantly decreased chance to became long-lived in an allele dose-dependent manner (p = 1.090×10–6 and 1.964×10–4 for SIRT2 and DRD2, respectively). The results indicate that the individual aging phenotype may be affected by the variability of specific miRNA targeted regions, as shown for SIRT2 and DRD2, and may suggest further studies to analyze the variability of gene expression regulation as a modulator of aging phenotypes.
Article
Full-text available
The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts. There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest. ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Article
Full-text available
Background. The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies. Methods. We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity. Results. In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10-7) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10-8) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10-10). Conclusions. We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants. © 2014 © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected] /* */
Article
Full-text available
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10-94<P<5×10-8, odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2×10-23 < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.
Article
Full-text available
Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10-7 for BMI, 1.80×10-6 for FM, and 5.29×10-4 for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10-3 to 4.94×10-2). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.
Article
Full-text available
The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases≥90 years.We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR=1.10, P =1.74 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR=0.72, P=3.40 x 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n=34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR=0.95, P=0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
Article
Growth pathways play key roles in longevity. The present study tested single-nucleotide polymorphisms (SNPs) in the connective tissue growth factor gene (CTGF) and the epidermal growth factor receptor gene (EGFR) for association with longevity. Comparison of allele and genotype frequencies of 12 CTGF SNPs and 41 EGFR SNPs between 440 American men of Japanese ancestry aged ≥95 years and 374 men of average life span revealed association with longevity at the p < .05 level for 2 SNPs in CTGF and 7 in EGFR. Two in CTGF and two in EGFR remained significant after Bonferroni correction. The SNPs of both CTGF and EGFR were in a haplotype block in each respective gene. Haplotype analysis confirmed the suggestive association found by χ2 analysis. We noted an excess of heterozygotes among the longevity cases, consistent with heterozygote advantage in living to extreme old age. No associations of the most significant SNPs were observed in whites or Koreans. In conclusion, the present findings indicate that genetic variation in CTGF and EGFR may contribute to the attainment of extreme old age in Japanese. More research is needed to confirm that genetic variation in CTGF and EGFR contributes to the attainment of extreme old age across human populations.