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Linkage and association of successful aging to the 6q25 region in large Amish kindreds

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Abstract

Successful aging (SA) is a multidimensional phenotype involving living to older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting polymorphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we examined 263 cognitively intact Amish individuals age 80 and older (74 SA and 189 “normally aged”) all of whom are part of a single 13-generation pedigree. A genome-wide association study of 630,309 autosomal single nucleotide polymorphisms (SNPs) was performed and analyzed for linkage using multipoint analyses and for association using the modified quasi-likelihood score test. There was evidence for linkage on 6q25-27 near the fragile site FRA6E region with a dominant model maximum multipoint heterogeneity LOD score = 3.2. The 1-LOD-down support interval for this linkage contained one SNP for which there was regionally significant evidence of association (rs205990, p = 2.36 × 10−5). This marker survived interval-wide Bonferroni correction for multiple testing and was located between the genes QKI and PDE10A. Other areas of chromosome 6q25-q27 (including the FRA6E region) contained several SNPs associated with SA (minimum p = 2.89 × 10−6). These findings suggest potentially novel genes in the 6q25-q27 region linked and associated with SA in the Amish; however, these findings should be verified in an independent replication cohort.

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References

  • Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  PubMed  CAS  Google Scholar 

  • Agarwala R, Biesecker LG, Schaffer AA (2003) Anabaptist genealogy database. Am J Med Genet C Semin Med Genet 121C:32–37

    Article  PubMed  Google Scholar 

  • Arcos-Burgos M, Muenke M (2002) Genetics of population isolates. Clin Genet 61:233–247

    Article  PubMed  CAS  Google Scholar 

  • Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 96:412–418

    Article  PubMed  CAS  Google Scholar 

  • Arnaud-Lopez L, Usala G, Ceresini G, Mitchell BD, Pilia MG, Piras MG, Sestu N, Maschio A, Busonero F, Albai G, Dei M, Lai S, Mulas A, Crisponi L, Tanaka T, Bandinelli S, Guralnik JM, Loi A, Balaci L, Sole G, Prinzis A, Mariotti S, Shuldiner AR, Cao A, Schlessinger D, Uda M, Abecasis GR, Nagaraja R, Sanna S, Naitza S (2008) Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet 82:1270–1280

    Article  PubMed  CAS  Google Scholar 

  • Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I (2009a) Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 94:1251–1254

    Article  PubMed  CAS  Google Scholar 

  • Atzmon G, Barzilai N, Surks MI, Gabriely I (2009b) Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab 94:4768–4775

    Article  PubMed  CAS  Google Scholar 

  • Banasik K, Ribel-Madsen R, Gjesing AP, Wegner L, Andersson A, Poulsen P, Borglykke A, Witte DR, Pedersen O, Hansen T, Vaag A (2011) The FOXO3A rs2802292 G-allele associates with improved peripheral and hepatic insulin sensitivity and increased skeletal muscle-FOXO3A mRNA expression in twins. J Clin Endocrinol Metab 96:E119–E124

    Article  PubMed  CAS  Google Scholar 

  • Capurso C, Solfrizzi V, D’Introno A, Colacicco AM, Capurso SA, Semeraro C, Capurso A, Panza F (2004) Interleukin 6-174G/C promoter gene polymorphism in centenarians: no evidence of association with human longevity or interaction with apolipoprotein E alleles. Exp Gerontol 39:1109–1114

    Article  PubMed  CAS  Google Scholar 

  • Carmelli D, Kelly-Hayes M, Wolf PA, Swan GE, Jack LM, Reed T, Guralnik JM (2000) The contribution of genetic influences to measures of lower-extremity function in older male twins. J Gerontol A Biol Sci Med Sci 55:B49–B53

    Article  PubMed  CAS  Google Scholar 

  • Cellini E, Nacmias B, Olivieri F, Ortenzi L, Tedde A, Bagnoli S, Petruzzi C, Franceschi C, Sorbi S (2005) Cholesteryl ester transfer protein (CETP) I405V polymorphism and longevity in Italian centenarians. Mech Ageing Dev 126:826–828

    Article  PubMed  CAS  Google Scholar 

  • Cheng Q, Zhao Y, Lawson WE, Polosukhin VV, Johnson JE, Blackwell TS, Gailani D (2005) The effects of intrinsic pathway protease deficiencies on plasminogen-deficient mice. Blood 106:3055–3057

    Article  PubMed  CAS  Google Scholar 

  • Chung WH, Dao RL, Chen LK, Hung SI (2010) The role of genetic variants in human longevity. Ageing Res Rev 9(Suppl 1):S67–S78

    Article  PubMed  CAS  Google Scholar 

  • Deelen J, Beekman M, Uh HW, Helmer Q, Kuningas M, Christiansen L, Kremer D, van der Breggen R, Suchiman HE, Lakenberg N, van den Akker EB, Passtoors WM, Tiemeier H, van Heemst D, de Craen AJ, Rivadeneira F, de Geus EJ, Perola M, van der Ouderaa FJ, Gunn DA, Boomsma DI, Uitterlinden AG, Christensen K, van Duijn CM, Heijmans BT, Houwing-Duistermaat JJ, Westendorp RG, Slagboom PE (2011) Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell 10:686–698

    Article  PubMed  CAS  Google Scholar 

  • Depp CA, Jeste DV (2006) Definitions and predictors of successful aging: a comprehensive review of larger quantitative studies. Am J Geriatr Psychiatry 14:6–20

    Article  PubMed  Google Scholar 

  • Epstein MP, Duren WL, Boehnke M (2000) Improved inference of relationship for pairs of individuals. Am J Hum Genet 67:1219–1231

    PubMed  CAS  Google Scholar 

  • Farrer LA, Conneally PM, Yu PL (1984) The natural history of Huntington’s disease: possible role of “aging genes”. Am J Med Genet 18:115–123

    Article  PubMed  CAS  Google Scholar 

  • Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV (2007) Successful aging: from phenotype to genotype. Biol Psychiatry 62:282–293

    Article  PubMed  CAS  Google Scholar 

  • Hahs DW, McCauley JL, Crunk AE, McFarland LL, Gaskell PC, Jiang L, Slifer SH, Vance JM, Scott WK, Welsh-Bohmer KA, Johnson SR, Jackson CE, Pericak-Vance MA, Haines JL (2006) A genome-wide linkage analysis of dementia in the Amish. Am J Med Genet B Neuropsychiatr Genet 141B:160–166

    Article  PubMed  Google Scholar 

  • Katz S (1983) Assessing self-maintenance: activities of daily living, mobility, and instrumental activities of daily living. J Am Geriatr Soc 31:721–727

    PubMed  CAS  Google Scholar 

  • Kehler J (2011) PDE10A inhibitors: novel therapeutic drugs for schizophrenia. Curr Pharm Des 17:137–150

    Article  PubMed  CAS  Google Scholar 

  • Khachaturian AS, Gallo JJ, Breitner JC (2000) Performance characteristics of a two-stage dementia screen in a population sample. J Clin Epidemiol 53:531–540

    Article  PubMed  CAS  Google Scholar 

  • Kleiman RJ, Kimmel LH, Bove SE, Lanz TA, Harms JF, Romegialli A, Miller KS, Willis A, des Estages S, Kuhn M, Schmidt CJ (2011) Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington’s disease. J Pharmacol Exp Ther 336:64–76

    Article  PubMed  CAS  Google Scholar 

  • Kleindorp R, Flachsbart F, Puca AA, Malovini A, Schreiber S, Nebel A (2011) Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans. Aging Cell 10:622–628

    Article  PubMed  CAS  Google Scholar 

  • Korn JM, Kuruvilla FG, McCarroll SA, Wysoker A, Nemesh J, Cawley S, Hubbell E, Veitch J, Collins PJ, Darvishi K, Lee C, Nizzari MM, Gabriel SB, Purcell S, Daly MJ, Altshuler D (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40:1253–1260

    Article  PubMed  CAS  Google Scholar 

  • Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9:179–186

    Article  PubMed  CAS  Google Scholar 

  • Li C, Wu W, Jin H, Zhang X, Xue H, He Y, Xiao S, Jeste DV, Zhang M (2006) Successful aging in Shanghai, China: definition, distribution, and related factors. Int Psychogeriatr 18:551–563

    Google Scholar 

  • Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18:4897–4904

    Article  PubMed  CAS  Google Scholar 

  • Liu F, Kirichenko A, Axenovich TI, van Duijn CM, Aulchenko YS (2008) An approach for cutting large and complex pedigrees for linkage analysis. Eur J Hum Genet 16:854–860

    Article  PubMed  CAS  Google Scholar 

  • Lunetta KL, D’Agostino RB Sr, Karasik D, Benjamin EJ, Guo CY, Govindaraju R, Kiel DP, Kelly-Hayes M, Massaro JM, Pencina MJ, Seshadri S, Murabito JM (2007) Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham study. BMC Med Genet 8(Suppl 1):S13

    Article  PubMed  Google Scholar 

  • Matise TC, Chen F, Chen W, De La Vega FM, Hansen M, He C, Hyland FC, Kennedy GC, Kong X, Murray SS, Ziegle JS, Stewart WC, Buyske S (2007) A second-generation combined linkage physical map of the human genome. Genome Res 17:1783–1786

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin SJ, Connell CM, Heeringa SG, Li LW, Roberts JS (2010) Successful aging in the United States: prevalence estimates from a national sample of older adults. J Gerontol B Psychol Sci Soc Sci 65B:216–226

    Article  PubMed  Google Scholar 

  • Nagi SZ (1976) An epidemiology of disability among adults in the United States. Milbank Mem Fund Q Health Soc 54:439–467

    Article  PubMed  CAS  Google Scholar 

  • Naumova E, Mihaylova A, Ivanova M, Michailova S, Penkova K, Baltadjieva D (2004) Immunological markers contributing to successful aging in Bulgarians. Exp Gerontol 39:637–644

    Article  PubMed  CAS  Google Scholar 

  • Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanche H, Junge O, Wittig M, Ellinghaus D, Flachsbart F, Wichmann HE, Meitinger T, Nikolaus S, Franke A, Krawczak M, Lathrop M, Schreiber S (2011) A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals. Mech Ageing Dev 132:324–330

    Article  PubMed  CAS  Google Scholar 

  • Newman AB, Walter S, Lunetta KL, Garcia ME, Slagboom PE, Christensen K, Arnold AM, Aspelund T, Aulchenko YS, Benjamin EJ, Christiansen L, D’Agostino RB Sr, Fitzpatrick AL, Franceschini N, Glazer NL, Gudnason V, Hofman A, Kaplan R, Karasik D, Kelly-Hayes M, Kiel DP, Launer LJ, Marciante KD, Massaro JM, Miljkovic I, Nalls MA, Hernandez D, Psaty BM, Rivadeneira F, Rotter J, Seshadri S, Smith AV, Taylor KD, Tiemeier H, Uh HW, Uitterlinden AG, Vaupel JW, Walston J, Westendorp RG, Harris TB, Lumley T, van Duijn CM, Murabito JM (2010) A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. J Gerontol A Biol Sci Med Sci 65:478–487

    Article  PubMed  Google Scholar 

  • Pericak-Vance MA, Johnson CC, Rimmler JB, Saunders AM, Robinson LC, D’Hondt EG, Jackson CE, Haines JL (1996) Alzheimer’s disease and apolipoprotein E-4 allele in an Amish population. Ann Neurol 39:700–704

    Article  PubMed  CAS  Google Scholar 

  • Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, Bogan H, Joyce E, Brewster S, Kunkel L, Puca A (2002) Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A 99:8442–8447

    Article  PubMed  CAS  Google Scholar 

  • Poduslo SE, Huang R, Spiro A III (2009) A genome screen of successful aging without cognitive decline identifies LRP1B by haplotype analysis. Am J Med Genet B Neuropsychiatr Genet 153B:114–119

    Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  • Rosow I, Breslau N (1966) A Guttman health scale for the aged. J Gerontol 21:556–559

    Article  PubMed  CAS  Google Scholar 

  • Rowe JW, Kahn RL (1997) Successful aging. Gerontologist 37:433–440

    Article  PubMed  CAS  Google Scholar 

  • Seeman TE, Charpentier PA, Berkman LF, Tinetti ME, Guralnik JM, Albert M, Blazer D, Rowe JW (1994) Predicting changes in physical performance in a high-functioning elderly cohort: MacArthur studies of successful aging. J Gerontol 49:M97–108

    Article  PubMed  CAS  Google Scholar 

  • Snejdrlova M, Kalvach Z, Topinkova E, Vrablik M, Prochazkova R, Kvasilova M, Lanska V, Zlatohlavek L, Prusikova M, Ceska R (2011) APOE polymorphism as a potential determinant of functional fitness in the elderly regardless of nutritional status. Neuro Endocrinol Lett 32:51–54

    PubMed  CAS  Google Scholar 

  • Swedlund AC, Meindl RS, Nydon J, Gradie M (1983) Family patterns in longevity and longevity patterns of the family. Hum Biol 55:115–129

    PubMed  CAS  Google Scholar 

  • Taioli E, Mari D, Franceschi C, Bonafe M, Monti D, Bertolini S, Marinelli D, Garte S (2001) Polymorphisms of drug-metabolizing enzymes in healthy nonagenarians and centenarians: difference at GSTT1 locus. Biochem Biophys Res Commun 280:1389–1392

    Article  PubMed  CAS  Google Scholar 

  • Teng EL, Chui HC (1987) The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 48:314–318

    PubMed  CAS  Google Scholar 

  • Thornton T, McPeek MS (2007) Case–control association testing with related individuals: a more powerful quasi-likelihood score test. Am J Hum Genet 81:321–337

    Article  PubMed  CAS  Google Scholar 

  • US Census Bureau Population Division and Housing and Household Economic Statistics Division. National Population Projections. 2001. Ref Type: Report

  • van der Walt JM, Scott WK, Slifer S, Gaskell PC, Martin ER, Welsh-Bohmer K, Creason M, Crunk A, Fuzzell D, McFarland L, Kroner CC, Jackson CE, Haines JL, Pericak-Vance MA (2005) Maternal lineages and Alzheimer disease risk in the old order Amish. Hum Genet 118:115–122

    Article  PubMed  CAS  Google Scholar 

  • Velez Edwards D, Gilbert J, Jiang L, Gallins P, Caywood L, Creason M, Fuzzell D, Knebusch C, Jackson C, Pericak-Vance M, Haines J, Scott W (2011) Successful aging shows linkage to chromosome 6, 7, and 14 in the Amish. Ann Hum Genet 75(4):516–528

    Article  Google Scholar 

  • Yesavage JA (1988) Geriatric depression scale. Psychopharmacol Bull 24:709–711

    PubMed  CAS  Google Scholar 

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Acknowledgments

We acknowledge the of the Vanderbilt CHGR DNA Resources core for processing some of the samples. Some of the samples used in this study were collected while WKS, JRG, and MAP-V were faculty members at Duke University. This work supported by NIH grants AG019085 to Jonathan L. Haines and AG019726 to William K. Scott.

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  1. Digna R. Velez Edwards

    Present address: Center for Human Genetics Research, Vanderbilt University Epidemiology Center, Institute of Medicine and Public Health, Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA

Authors and Affiliations

  1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, Room 414, Miami, FL, 33136, USA

    Digna R. Velez Edwards, John R. Gilbert, James E. Hicks, Jamie L. Myers, Shengru Guo, Paul J. Gallins, Ioanna Konidari, Laura Caywood, Lori Reinhart-Mercer, Margaret A. Pericak-Vance & William K. Scott

  2. Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    Lan Jiang, Anna C. Cummings, Denise Fuzzell, Claire Knebusch, Renee Laux & Jonathan L. Haines

  3. Carmel, IN, USA

    Charles E. Jackson

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  1. Digna R. Velez Edwards
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Online Resource Fig. 1

Log quantile–quantile (Q–Q) p value plots. This plot shows the distribution of observed MQLS statistic p values plotted against the expected p values under the null hypothesis of no association for the MQLS analyses of 74 SA and 189 controls. The diagonal line shows the values expected under the null hypothesis (PDF 21 kb)

Online Resource Fig. 2

Manhattan plot of all MQLS associations. The negative log of the MQLS p value is on the y-axis and the base pair position is on the x-axis across all autosomal SNPs examined. The red line indicates the p value cutoff for 5.00 × 10−5 and the blue line indicates the 5.00 × 10−2 cutoff (PDF 101 kb)

Online Resource Fig. 3

Linkage disequilibrium plot of SNPs in FRA6E region. All figures are oriented 5′ to 3′, right to left, relative to the gene orientation on the minus strand. r 2 is indicated in percentages within squares in the LD plot, with solid blocks without numbers indicating perfect LD, where r 2 = 1. Strong LD is indicated by dark gray, while white indicates low LD. LD blocks were created with the default algorithm in HaploView that creates 95 % confidence bounds on D′ considered being in strong LD where 95 % of the comparisons made are informative. The haplotype blocks were created using HaploView program, version 4.1 (PDF 31 kb)

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Edwards, D.R.V., Gilbert, J.R., Hicks, J.E. et al. Linkage and association of successful aging to the 6q25 region in large Amish kindreds. AGE 35, 1467–1477 (2013). https://doi.org/10.1007/s11357-012-9447-1

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