A genome-wide association study of aging

Stefan Walter; Gil Atzmon; Ellen W. Demerath; Melissa E. Garcia; Robert C. Kaplan; Meena Kumari; Kathryn L. Lunetta; Yuri Milaneschi; Toshiko Tanaka; Gregory J. Tranah; Uwe Völker; Lei Yu; Alice Arnold; Emelia J. Benjamin; Reiner Biffar; Aron S. Buchman; Eric Boerwinkle; David Couper; Philip L. De Jager; Denis A. Evans; Tamara B. Harris; Wolfgang Hoffmann; Albert Hofman; David Karasik; Douglas P. Kiel; Thomas Kocher; Maris Kuningas; Lenore J. Launer; Kurt K. Lohman; Pamela L. Lutsey; Johan Mackenbach; Kristin Marciante; Bruce M. Psaty; Eric M. Reiman; Jerome I. Rotter; Sudha Seshadri; Michelle D. Shardell; Albert V. Smith; Cornelia van Duijn; Jeremy Walston; M. Carola Zillikens; Stefania Bandinelli; Sebastian E. Baumeister; David A. Bennett; Luigi Ferrucci; Vilmundur Gudnason; Mika Kivimaki; Yongmei Liu; Joanne M. Murabito; Anne B. Newman; Henning Tiemeier; Nora Franceschini

doi:10.1016/j.neurobiolaging.2011.05.026

A genome-wide association study of aging

Stefan Walter, Gil Atzmon, Ellen W. Demerath, Melissa E. Garcia, Robert C. Kaplan, Meena Kumari, Kathryn L. Lunetta, Yuri Milaneschi, Toshiko Tanaka, Gregory J. Tranah, Uwe Völker, Lei Yu, Alice Arnold, Emelia J. Benjamin, Reiner Biffar, Aron S. Buchman, Eric Boerwinkle, David Couper, Philip L. De Jager, Denis A. EvansTamara B. Harris, Wolfgang Hoffmann, Albert Hofman, David Karasik, Douglas P. Kiel, Thomas Kocher, Maris Kuningas, Lenore J. Launer, Kurt K. Lohman, Pamela L. Lutsey, Johan Mackenbach, Kristin Marciante, Bruce M. Psaty, Eric M. Reiman, Jerome I. Rotter, Sudha Seshadri, Michelle D. Shardell, Albert V. Smith, Cornelia van Duijn, Jeremy Walston, M. Carola Zillikens, Stefania Bandinelli, Sebastian E. Baumeister, David A. Bennett, Luigi Ferrucci, Vilmundur Gudnason, Mika Kivimaki, Yongmei Liu, Joanne M. Murabito, Anne B. Newman, Henning Tiemeier, Nora Franceschini

Research output: Contribution to journal › Article › peer-review

Abstract

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10^-8). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10^-5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

Original language	English
Pages (from-to)	2109.e15-2109.e28
Journal	Neurobiology of Aging
Volume	32
Issue number	11
DOIs	https://doi.org/10.1016/j.neurobiolaging.2011.05.026
State	Published - Nov 2011
Externally published	Yes

Bibliographical note

Funding Information:
Cardiovascular Health Study: The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute , the National Institute of Aging R01 AG031890 with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org/pi.htm . DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

Funding Information:
Age, Gene/Environment Susceptibility -Reykjavik Study: The Age, Gene/Environment Susceptibility-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA IRP Laboratory of Neurogenetics.

Funding Information:
The Longevity Consortium, funded by the National Institute of Aging , grant number U19 AG023122 , provided administrative resources to CHARGE investigators for this phenotype as well as scientific opportunity funds for de novo genotyping of the 5 selected SNPs in the ELSA and Whitehall II replication studies.

Funding Information:
Framingham Heart Study: Phenotype-genotype analyses were supported by the National Institute of Aging grant number R01AG029451 (PI: JMM). The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Dr. Kiel's effort as well as all hip fracture data from the Framingham Osteoporosis Study was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging ; R01 AR/AG 41398 . This research was additionally supported by the following grants: AG033193, AG081220, NS17950, P30AG013846, 1R01AG028321.

Funding Information:
Religious Order Study: Grants P30AG10161 , R01AG15819 , and R01AG30146 from the National Institute on Aging , and the Translation Genomics Research Institute.

Funding Information:
Health, Aging and Body Composition: This research is supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, N01AG62106 and NIA grant 1R03AG032498-01 . The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C.

Funding Information:
Invecchiare nel Chianti: The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336).

Funding Information:
Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions.

Funding Information:
Rotterdam Study: The Rotterdam Study is supported by Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (NWO) (904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419, 175.010.2005.011, 911-03-012 and 017.106.370); Netspar—Living longer for a good health; the Erasmus Medical Center, and Erasmus University in Rotterdam; the Netherlands Organization for Health Research and Development, the Netherlands Research Institute for Diseases in the Elderly; the Dutch Ministry of Education, Culture and Science, and the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam, the Netherlands.

Funding Information:
Whitehall II: Whitehall II has been supported by grants from the Medical Research Council ; Economic and Social Research Council ; British Heart Foundation ; Health and Safety Executive ; Department of Health ; National Heart Lung and Blood Institute ( HL36310 ), US NIH National Institute on Aging ( AG13196 ), US NIH Agency for Health Care Policy Research ( HS06516 ); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health .

Funding Information:
Study of Health in Pomerania: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012 ) and a joint grant from Siemens Healthcare , Erlangen, Germany and the Federal State of Mecklenburg , West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens AG.

Keywords

Aging
Brain aging
Disease-free survival
Genome-wide association analysis
Longevity
Mortality

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.neurobiolaging.2011.05.026

Cite this

Walter, S., Atzmon, G., Demerath, E. W., Garcia, M. E., Kaplan, R. C., Kumari, M., Lunetta, K. L., Milaneschi, Y., Tanaka, T., Tranah, G. J., Völker, U., Yu, L., Arnold, A., Benjamin, E. J., Biffar, R., Buchman, A. S., Boerwinkle, E., Couper, D., De Jager, P. L., ... Franceschini, N. (2011). A genome-wide association study of aging. Neurobiology of Aging, 32(11), 2109.e15-2109.e28. https://doi.org/10.1016/j.neurobiolaging.2011.05.026

@article{bcf0118a37e949b48f4d3ea9f7eba58c,

title = "A genome-wide association study of aging",

abstract = "Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10-8). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10-5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.",

keywords = "Aging, Brain aging, Disease-free survival, Genome-wide association analysis, Longevity, Mortality",

author = "Stefan Walter and Gil Atzmon and Demerath, {Ellen W.} and Garcia, {Melissa E.} and Kaplan, {Robert C.} and Meena Kumari and Lunetta, {Kathryn L.} and Yuri Milaneschi and Toshiko Tanaka and Tranah, {Gregory J.} and Uwe V{\"o}lker and Lei Yu and Alice Arnold and Benjamin, {Emelia J.} and Reiner Biffar and Buchman, {Aron S.} and Eric Boerwinkle and David Couper and {De Jager}, {Philip L.} and Evans, {Denis A.} and Harris, {Tamara B.} and Wolfgang Hoffmann and Albert Hofman and David Karasik and Kiel, {Douglas P.} and Thomas Kocher and Maris Kuningas and Launer, {Lenore J.} and Lohman, {Kurt K.} and Lutsey, {Pamela L.} and Johan Mackenbach and Kristin Marciante and Psaty, {Bruce M.} and Reiman, {Eric M.} and Rotter, {Jerome I.} and Sudha Seshadri and Shardell, {Michelle D.} and Smith, {Albert V.} and {van Duijn}, Cornelia and Jeremy Walston and Zillikens, {M. Carola} and Stefania Bandinelli and Baumeister, {Sebastian E.} and Bennett, {David A.} and Luigi Ferrucci and Vilmundur Gudnason and Mika Kivimaki and Yongmei Liu and Murabito, {Joanne M.} and Newman, {Anne B.} and Henning Tiemeier and Nora Franceschini",

note = "Funding Information: Cardiovascular Health Study: The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute , the National Institute of Aging R01 AG031890 with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org/pi.htm . DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: Age, Gene/Environment Susceptibility -Reykjavik Study: The Age, Gene/Environment Susceptibility-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA IRP Laboratory of Neurogenetics. Funding Information: The Longevity Consortium, funded by the National Institute of Aging , grant number U19 AG023122 , provided administrative resources to CHARGE investigators for this phenotype as well as scientific opportunity funds for de novo genotyping of the 5 selected SNPs in the ELSA and Whitehall II replication studies. Funding Information: Framingham Heart Study: Phenotype-genotype analyses were supported by the National Institute of Aging grant number R01AG029451 (PI: JMM). The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Dr. Kiel's effort as well as all hip fracture data from the Framingham Osteoporosis Study was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging ; R01 AR/AG 41398 . This research was additionally supported by the following grants: AG033193, AG081220, NS17950, P30AG013846, 1R01AG028321. Funding Information: Religious Order Study: Grants P30AG10161 , R01AG15819 , and R01AG30146 from the National Institute on Aging , and the Translation Genomics Research Institute. Funding Information: Health, Aging and Body Composition: This research is supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, N01AG62106 and NIA grant 1R03AG032498-01 . The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Funding Information: Invecchiare nel Chianti: The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). Funding Information: Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions. Funding Information: Rotterdam Study: The Rotterdam Study is supported by Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (NWO) (904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419, 175.010.2005.011, 911-03-012 and 017.106.370); Netspar—Living longer for a good health; the Erasmus Medical Center, and Erasmus University in Rotterdam; the Netherlands Organization for Health Research and Development, the Netherlands Research Institute for Diseases in the Elderly; the Dutch Ministry of Education, Culture and Science, and the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam, the Netherlands. Funding Information: Whitehall II: Whitehall II has been supported by grants from the Medical Research Council ; Economic and Social Research Council ; British Heart Foundation ; Health and Safety Executive ; Department of Health ; National Heart Lung and Blood Institute ( HL36310 ), US NIH National Institute on Aging ( AG13196 ), US NIH Agency for Health Care Policy Research ( HS06516 ); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health . Funding Information: Study of Health in Pomerania: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012 ) and a joint grant from Siemens Healthcare , Erlangen, Germany and the Federal State of Mecklenburg , West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens AG. ",

year = "2011",

month = nov,

doi = "10.1016/j.neurobiolaging.2011.05.026",

language = "English",

volume = "32",

pages = "2109.e15--2109.e28",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier",

number = "11",

}

Walter, S, Atzmon, G, Demerath, EW, Garcia, ME, Kaplan, RC, Kumari, M, Lunetta, KL, Milaneschi, Y, Tanaka, T, Tranah, GJ, Völker, U, Yu, L, Arnold, A, Benjamin, EJ, Biffar, R, Buchman, AS, Boerwinkle, E, Couper, D, De Jager, PL, Evans, DA, Harris, TB, Hoffmann, W, Hofman, A, Karasik, D, Kiel, DP, Kocher, T, Kuningas, M, Launer, LJ, Lohman, KK, Lutsey, PL, Mackenbach, J, Marciante, K, Psaty, BM, Reiman, EM, Rotter, JI, Seshadri, S, Shardell, MD, Smith, AV, van Duijn, C, Walston, J, Zillikens, MC, Bandinelli, S, Baumeister, SE, Bennett, DA, Ferrucci, L, Gudnason, V, Kivimaki, M, Liu, Y, Murabito, JM, Newman, AB, Tiemeier, H & Franceschini, N 2011, 'A genome-wide association study of aging', Neurobiology of Aging, vol. 32, no. 11, pp. 2109.e15-2109.e28. https://doi.org/10.1016/j.neurobiolaging.2011.05.026

TY - JOUR

T1 - A genome-wide association study of aging

AU - Walter, Stefan

AU - Atzmon, Gil

AU - Demerath, Ellen W.

AU - Garcia, Melissa E.

AU - Kaplan, Robert C.

AU - Kumari, Meena

AU - Lunetta, Kathryn L.

AU - Milaneschi, Yuri

AU - Tanaka, Toshiko

AU - Tranah, Gregory J.

AU - Völker, Uwe

AU - Yu, Lei

AU - Arnold, Alice

AU - Benjamin, Emelia J.

AU - Biffar, Reiner

AU - Buchman, Aron S.

AU - Boerwinkle, Eric

AU - Couper, David

AU - De Jager, Philip L.

AU - Evans, Denis A.

AU - Harris, Tamara B.

AU - Hoffmann, Wolfgang

AU - Hofman, Albert

AU - Karasik, David

AU - Kiel, Douglas P.

AU - Kocher, Thomas

AU - Kuningas, Maris

AU - Launer, Lenore J.

AU - Lohman, Kurt K.

AU - Lutsey, Pamela L.

AU - Mackenbach, Johan

AU - Marciante, Kristin

AU - Psaty, Bruce M.

AU - Reiman, Eric M.

AU - Rotter, Jerome I.

AU - Seshadri, Sudha

AU - Shardell, Michelle D.

AU - Smith, Albert V.

AU - van Duijn, Cornelia

AU - Walston, Jeremy

AU - Zillikens, M. Carola

AU - Bandinelli, Stefania

AU - Baumeister, Sebastian E.

AU - Bennett, David A.

AU - Ferrucci, Luigi

AU - Gudnason, Vilmundur

AU - Kivimaki, Mika

AU - Liu, Yongmei

AU - Murabito, Joanne M.

AU - Newman, Anne B.

AU - Tiemeier, Henning

AU - Franceschini, Nora

N1 - Funding Information: Cardiovascular Health Study: The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute , the National Institute of Aging R01 AG031890 with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org/pi.htm . DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: Age, Gene/Environment Susceptibility -Reykjavik Study: The Age, Gene/Environment Susceptibility-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA IRP Laboratory of Neurogenetics. Funding Information: The Longevity Consortium, funded by the National Institute of Aging , grant number U19 AG023122 , provided administrative resources to CHARGE investigators for this phenotype as well as scientific opportunity funds for de novo genotyping of the 5 selected SNPs in the ELSA and Whitehall II replication studies. Funding Information: Framingham Heart Study: Phenotype-genotype analyses were supported by the National Institute of Aging grant number R01AG029451 (PI: JMM). The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Dr. Kiel's effort as well as all hip fracture data from the Framingham Osteoporosis Study was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging ; R01 AR/AG 41398 . This research was additionally supported by the following grants: AG033193, AG081220, NS17950, P30AG013846, 1R01AG028321. Funding Information: Religious Order Study: Grants P30AG10161 , R01AG15819 , and R01AG30146 from the National Institute on Aging , and the Translation Genomics Research Institute. Funding Information: Health, Aging and Body Composition: This research is supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, N01AG62106 and NIA grant 1R03AG032498-01 . The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Funding Information: Invecchiare nel Chianti: The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). Funding Information: Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions. Funding Information: Rotterdam Study: The Rotterdam Study is supported by Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (NWO) (904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419, 175.010.2005.011, 911-03-012 and 017.106.370); Netspar—Living longer for a good health; the Erasmus Medical Center, and Erasmus University in Rotterdam; the Netherlands Organization for Health Research and Development, the Netherlands Research Institute for Diseases in the Elderly; the Dutch Ministry of Education, Culture and Science, and the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam, the Netherlands. Funding Information: Whitehall II: Whitehall II has been supported by grants from the Medical Research Council ; Economic and Social Research Council ; British Heart Foundation ; Health and Safety Executive ; Department of Health ; National Heart Lung and Blood Institute ( HL36310 ), US NIH National Institute on Aging ( AG13196 ), US NIH Agency for Health Care Policy Research ( HS06516 ); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health . Funding Information: Study of Health in Pomerania: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012 ) and a joint grant from Siemens Healthcare , Erlangen, Germany and the Federal State of Mecklenburg , West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens AG.

PY - 2011/11

Y1 - 2011/11

N2 - Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10-8). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10-5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

AB - Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10-8). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10-5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

KW - Aging

KW - Brain aging

KW - Disease-free survival

KW - Genome-wide association analysis

KW - Longevity

KW - Mortality

UR - http://www.scopus.com/inward/record.url?scp=80052641742&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2011.05.026

DO - 10.1016/j.neurobiolaging.2011.05.026

M3 - Article

C2 - 21782286

AN - SCOPUS:80052641742

SN - 0197-4580

VL - 32

SP - 2109.e15-2109.e28

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 11

ER -

A genome-wide association study of aging

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