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.
|Neurobiology of Aging
|Published - Nov 2011
Bibliographical noteFunding 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.
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.
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.
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.
Religious Order Study: Grants P30AG10161 , R01AG15819 , and R01AG30146 from the National Institute on Aging , and the Translation Genomics Research Institute.
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.
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).
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.
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.
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 .
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.
- Brain aging
- Disease-free survival
- Genome-wide association analysis