Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum

Nature Communications

Volumn 7, Issue , 2016, Pages

  Lu, Ake T ^a   Hannon, Eilis ^b   Levine, Morgan E ^a   Hao, Ke ^c   Crimmins, Eileen M ^d   Lunnon, Katie ^b   Kozlenkov, Alexey ^c,e   Mill, Jonathan ^b,f   Dracheva, Stella ^c,e   Horvath, Steve ^a,g  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF EXETER MEDICAL SCHOOL   (United Kingdom)

^c MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^e VETERANS AFFAIRS MEDICAL CENTER   (United States)

^f KING'S COLLEGE LONDON   (United Kingdom)

^g UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; DHX57 PROTEIN; MLST8 PROTEIN; UNCLASSIFIED DRUG; MLST8 PROTEIN, HUMAN; SIGNAL TRANSDUCING ADAPTOR PROTEIN;

AGING; BIOMARKER; BRAIN; DNA; GENE EXPRESSION; GENOME; METHYLATION; PHENOTYPE;

ADULT; AGE RELATED MACULAR DEGENERATION; AGED; ALZHEIMER DISEASE; ARTICLE; BRAIN REGION; CEREBELLUM; ENDOPHENOTYPE; EPIGENETICS; FEMALE; GENE EXPRESSION; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC VARIABILITY; HERITABILITY; HUMAN; MAJOR CLINICAL STUDY; MALE; PARKINSON DISEASE; SINGLE NUCLEOTIDE POLYMORPHISM; AGING; CELL LINE; GENE EXPRESSION REGULATION; GENE LINKAGE DISEQUILIBRIUM; GENETIC EPIGENESIS; GENETIC VARIATION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; METABOLISM; PHYSIOLOGY;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; AGING; CELL LINE; CEREBELLUM; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION; GENETIC VARIATION; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LINKAGE DISEQUILIBRIUM;

EID: 84957592590     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms10561     Document Type: Article

References (56)

1. Christensen, K., Johnson, T. E. & Vaupel, J. W. The quest for genetic determinants of human longevity: challenges and insights. Nat. Rev. Genet. 7, 436-448 (2006).
2. Deelen, J. et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell 10, 686-698 (2011).
3. Deelen, J. et al. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Hum. Mol. Genet. 23, 4420-4432 (2014).
4. Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987-13992 (2008).
5. Flachsbart, F. et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA 106, 2700-2705 (2009).
6. Morris, B. J., Willcox, D. C., Donlon, T. A. & Willcox, B. J. FOXO3: A Major Gene for Human Longevity - A Mini-Review. Gerontology 61, 515-525 (2015).
7. Fraga, M. F. & Esteller, M. Epigenetics and aging: the targets and the marks. Trends Genet. 23, 413-418 (2007).
8. Rando, Thomas A. & Chang, Howard Y. Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock. Cell 148, 46-57 (2012).
9. Benayoun, B. A., Pollina, E. A. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat. Rev. Mol. Cell Biol. 16, 593-610 (2015).
10. Rakyan, V. K. et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 20, 434-439 (2010).
11. Teschendorff, A. E. et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 20, 440-446 (2010).
12. Numata, S. et al. DNA methylation signatures in development and aging of the human prefrontal cortex. Am. J. Hum. Genet. 90, 260-272 (2012).
13. Alisch, R. S. et al. Age-associated DNA methylation in pediatric populations. Genome Res. 22, 623-632 (2012).
14. Johansson, A., Enroth, S. & Gyllensten, U. Continuous aging of the human DNA methylome throughout the human lifespan. PLoS ONE 8, e67378 (2013).
15. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
16. Horvath, S. et al. Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci USA 111, 15538-15543 (2014).
17. Horvath, S. et al. The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY) 7, 294-306 (2015).
18. Spiers, H. et al. Methylomic trajectories across human fetal brain development. Genome Res. 25, 338-352 (2015).
19. Marioni, R. et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16, 25 (2015).
20. Christiansen, L. et al. DNA methylation age is associated with mortality in a longitudinal Danish twin study. Aging Cell (2015) Nov 17. doi: 10.1111/acel.12421. [Epub ahead of print].
21. Horvath, S. et al. Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging (Albany NY) 7, 1159-1170 (2015).
22. Marioni, R. E. et al. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int. J. Epidemiol. 44, 1388-1396 (2015).
23. Horvath, S. & Ritz, B. R. Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients. Aging (Albany NY) 7, 1130-1142 (2015).
24. Levine, M., Lu, A., Bennett, D. & Horvath, S. Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning. Aging (Albany NY) 7, 1198-1211 (2015).
25. Horvath, S. et al. Accelerated Epigenetic Aging in Down Syndrome. Aging Cell 14, 491-495 (2015).
26. Horvath, S. & Levine, A. J. HIV-1 infection accelerates age according to the epigenetic clock. J. Infect. Dis. 212, 1563-1573 (2015).
27. Lee, S. H., Wray, N. R., Goddard, M. E. & Visscher, P. M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294-305 (2011).
28. Visscher, P. M. et al. Statistical power to detect genetic (co)variance of complex traits using SNP data in unrelated samples. PLoS Genet. 10, e1004269 (2014).
29. Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190-2191 (2010).
30. Roadmap Epigenomics, C. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317-330 (2015).
31. EncodeProject. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74 (2012).
32. Ernst, J. & Kellis, M. Large-scale imputation of epigenomic datasets for systematic annotation of diverse human tissues. Nat. Biotechnol. 33, 364-376 (2015).
33. Ramasamy, A. et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17, 1418-1428 (2014).
34. Segre, A. V., Groop, L., Mootha, V. K., Daly, M. J. & Altshuler, D. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 6, e1001058 (2010).
35. Fritsche, L. G. et al. Seven new loci associated with age-related macular degeneration. Nat. Genet. 45, 433-439 439e1-2 (2013).
36. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452-1458 (2013).
37. Simon-Sanchez, J. et al. Genome-Wide Association Study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308-1312 (2009).
38. Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).
39. Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-1196 (2005).
40. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392-395 (2009).
41. Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980-989 (2013).
42. Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338-345 (2013).
43. Gibbs, J. R. et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 6, e1000952 (2010).
44. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575 (2007).
45. Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904-909 (2006).
46. Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G. R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955-959 (2012).
47. Howie, B. N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
48. O'Connell, J. et al. A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness. PLoS Genet. 10, e1004234 (2014).
49. Pruim, R. J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336-2337 (2010).
50. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43-49 (2011).
51. Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008).
52. Lunnon, K. et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat. Neurosci. 17, 1164-1170 (2014).
53. Zhang, D. et al. Genetic control of individual differences in gene-specific methylation in human brain. Am. J. Hum. Genet. 86, 411-419 (2010).
54. Pidsley, R. et al. Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol. 15, 483 (2014).
55. Hernandez, D. et al. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum. Mol. Genet. 20, 1164-1172 (2011).
56. Di Narzo, A. F. et al. A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum. Mol. Genet. 23, 4801-4813 (2014).