Genetic signatures of exceptional longevity in humans.

Authors: Sebastiani P; Solovieff N; Dewan AT; Walsh KM; Puca A; Hartley SW; Melista E; Andersen S; Dworkis DA; Wilk JB; Myers RH; Steinberg MH; Montano M; Baldwin CT; Hoh J; Perls TT

Abstract: Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.

Keywords: Aged; Aged, 80 and over; Aging/*genetics; Alleles; Bayes Theorem; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease/genetics; Genome, Human/*genetics; Genotype; Humans; Longevity/*genetics; Male; Models, Genetic; Models, Statistical; *Polymorphism, Single Nucleotide
Journal: PloS one
Volume: 7
Issue: 1
Pages: e29848
Date: Jan. 27, 2012
PMID: 22279548
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Citation:

Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT, Hoh J, Perls TT (2012) Genetic signatures of exceptional longevity in humans. PloS one 7: e29848.


Lifespan Factors:
  • WRN Werner syndrome, RecQ helicase-like
  • XDH xanthine dehydrogenase
  • APOE apolipoprotein E
  • TOMM40 translocase of outer mitochondrial membrane 40 homolog (yeast)

  • Longevity Variant Associations (p-value):
  • rs2075650 (2.36e-10)
  • rs1322048 (2.94e-06)
  • rs12629971 (1.9e-06)
  • rs1456669 (4.05e-06)
  • rs6801173 (8.16e-06)
  • rs337656 (5.74e-05)
  • rs997675 (1.41e-05)
  • rs2247549 (3.2e-05)
  • rs9899404 (1.09e-05)
  • rs1340573 (0.000391042)
  • rs4977756 (7.97e-06)
  • rs4073968 (1.24e-05)
  • rs147295 (3.67e-05)
  • rs4802234 (9.22e-06)
  • rs8083511 (0.000116571)
  • rs4871976 (4.49e-05)
  • rs651922 (4.75e-05)
  • rs4722094 (1.93e-05)
  • rs4285687 (2.58e-05)
  • rs3763305 (4.51e-05)
  • rs1063192 (1.66e-05)
  • rs12446827 (6.09e-05)
  • rs2738173 (3.46e-05)
  • rs1016013 (3.61e-05)
  • rs7825208 (0.000283011)
  • rs915179 (2.3666e-05)
  • rs829751 (3.73e-05)
  • rs2334207 (4.6e-05)
  • rs12585627 (0.000245656)
  • rs1568282 (6.78e-05)
  • rs17702471 (0.000147857)
  • rs6984496 (4.86e-05)
  • rs2758331 (2.92563e-05)
  • rs701176 (4.74e-05)
  • rs4245543 (8.06e-05)
  • rs7246865 (0.000164604)
  • rs9513192 (7.38e-05)
  • rs1412832 (4.55361e-05)
  • rs9557276 (4.6512e-05)
  • rs6812745 (0.000558765)
  • rs7155817 (0.000712544)
  • rs10084768 (0.000217915)
  • rs2061450 (0.000305085)
  • rs10483493 (5.9607e-05)
  • rs2252024 (0.003246428)
  • rs899430 (0.000199837)
  • rs6997589 (6.25058e-05)
  • rs11783247 (9.44e-05)
  • rs5758008 (0.000149614)
  • rs9530108 (0.00112398)
  • rs1505696 (9.4e-05)
  • rs7959761 (9.56e-05)
  • rs4363980 (0.000573964)
  • rs1016339 (0.000102714)
  • rs10505391 (0.000174848)
  • rs4461634 (0.00011101)
  • rs1002098 (0.000996526)
  • rs11063009 (0.000299811)
  • rs7800926 (0.000233438)
  • rs1834461 (0.000268937)
  • rs5754682 (0.000845348)
  • rs6443429 (0.000251569)
  • rs4933309 (0.000192679)
  • rs216148 (0.000577091)
  • rs1470196 (0.000498694)
  • rs452707 (0.000168845)
  • rs9308765 (0.001929876)
  • rs1858897 (0.00037609)
  • rs767478 (0.000379776)
  • rs828154 (0.000271698)
  • rs2866705 (0.000161045)
  • rs1042663 (0.000169165)
  • rs6105966 (0.000131258)
  • rs9397084 (0.000104307)
  • rs563384 (0.001036546)
  • rs277432 (9.12039e-05)
  • rs590211 (0.000131352)
  • rs303542 (0.004840178)
  • rs2432143 (0.000253461)
  • rs9977638 (0.000185861)
  • rs8003961 (0.005011434)
  • rs1800392 (0.000178635)
  • rs8018467 (0.000221726)
  • rs2660888 (6.6e-05)
  • rs6115865 (0.000361261)
  • rs4141153 (0.000605394)
  • rs11086106 (0.000263101)
  • rs2383722 (0.000224392)
  • rs2253363 (0.000103425)
  • rs982764 (0.000335327)
  • rs514217 (0.000200862)
  • rs2963154 (0.0010712)
  • rs11687681 (0.000162169)
  • rs336264 (0.002543704)
  • rs4902538 (0.000661578)
  • rs12044217 (0.000178067)
  • rs2880540 (0.002577381)
  • rs11610554 (0.000197788)
  • rs10190125 (0.000168452)
  • rs7853840 (0.000734871)
  • rs1368774 (0.000514797)
  • rs11211037 (0.000175183)
  • rs697887 (0.000133355)
  • rs2243115 (0.001736813)
  • rs751481 (0.000239399)
  • rs1860242 (0.000108341)
  • rs10923673 (0.000306382)
  • rs3904864 (0.000126238)
  • rs9652250 (0.00021962)
  • rs855137 (0.000219407)
  • rs10505561 (0.001026563)
  • rs12634249 (0.000686245)
  • rs1998536 (0.001028903)
  • rs8098316 (0.003214587)
  • rs17044026 (0.001286948)
  • rs1557967 (0.000791168)
  • rs765850 (0.000259753)
  • rs1525501 (0.002700303)
  • rs1389488 (0.000454652)
  • rs2679234 (0.000259129)
  • rs1991289 (0.000121161)
  • rs2014547 (0.000225714)
  • rs1429842 (0.000540019)
  • rs3804474 (0.000264519)
  • rs2312243 (0.005424222)
  • rs401974 (0.000301574)
  • rs2927261 (0.001146375)
  • rs4785393 (0.000253223)
  • rs7857137 (0.000239219)
  • rs4771711 (0.000278415)
  • rs12129750 (0.007897685)
  • rs4596036 (0.00066782)
  • rs10518725 (0.000207413)
  • rs3906146 (0.000260059)
  • rs4751140 (0.000268865)
  • rs12155014 (0.00080402)
  • rs10863373 (0.000408144)
  • rs2604294 (0.000250017)
  • rs1280396 (0.00099615)
  • rs10263457 (0.001203582)
  • rs4570560 (0.000318341)
  • rs8080728 (0.000240188)
  • rs158807 (0.000255625)
  • rs923520 (0.000572367)
  • rs10957071 (0.001369463)
  • rs11005328 (0.002342056)
  • rs750586 (0.000691992)
  • rs358256 (0.001136273)
  • rs3181360 (0.00045202)
  • rs10510828 (0.000311601)
  • rs7207422 (0.000206202)
  • rs2242653 (0.000314783)
  • rs1867102 (0.000178417)
  • rs7524519 (0.000256892)
  • rs10498342 (0.000765791)
  • rs1230155 (0.000611098)
  • rs2043270 (0.00761736)
  • rs6657655 (0.000883462)
  • rs3024239 (0.000323577)
  • rs804283 (0.000281268)
  • rs12489296 (0.000811597)
  • rs1503434 (0.000382535)
  • rs216493 (0.001543457)
  • rs12606250 (0.000412426)
  • rs7656234 (0.000700593)
  • rs1822590 (0.000286695)
  • rs12121466 (0.000251843)
  • rs10140519 (0.000397649)
  • rs11954180 (0.000517104)
  • rs4647992 (0.000608192)
  • rs924584 (0.000233448)
  • rs933664 (0.000212572)
  • rs9916344 (0.000353663)
  • rs10511330 (0.002831841)
  • rs3886917 (0.000693471)
  • rs11153598 (0.00214039)
  • rs567971 (0.000325676)
  • rs303006 (0.001507459)
  • rs2901840 (0.002147925)
  • rs1898422 (0.000323698)
  • rs10055012 (0.001722103)
  • rs1005321 (0.000337804)
  • rs4918255 (0.00063068)
  • rs3782415 (0.000284992)
  • rs7127390 (0.001091248)
  • rs954472 (0.001955516)
  • rs262883 (0.001201492)
  • rs1463990 (0.000227906)
  • rs11189119 (0.000496282)
  • rs882696 (0.002004329)
  • rs6104550 (0.000727911)
  • rs1189843 (0.000273667)
  • rs1796412 (0.000338358)
  • rs2277509 (0.000177945)
  • rs2304965 (0.000581052)
  • rs12353067 (0.001055027)
  • rs1922263 (0.003569024)
  • rs12621193 (0.000348029)
  • rs2722222 (0.001503657)
  • rs4497194 (0.006460551)
  • rs10512392 (0.000742667)
  • rs12341685 (0.004008145)
  • rs1377843 (0.000414112)
  • rs4952085 (0.000933537)
  • rs9378384 (0.000262449)
  • rs2660342 (0.000314442)
  • rs4240673 (0.000380806)
  • rs4237774 (0.000637699)
  • rs8073559 (0.000376185)
  • rs1550765 (0.001403886)
  • rs2331101 (0.000244422)
  • rs1395451 (0.004442126)
  • rs346119 (0.000482679)
  • rs2269475 (0.000435495)
  • rs6946852 (0.000659153)
  • rs2543356 (0.00253896)
  • rs2596230 (0.004485855)
  • rs1581035 (0.000444836)
  • rs4729049 (0.003946549)
  • rs3769583 (0.001342643)
  • rs12043001 (0.002958435)
  • rs11943045 (0.004524209)
  • rs894558 (0.004524209)
  • rs2075773 (0.00043588)
  • rs13125710 (0.000571984)
  • rs2158860 (0.000446888)
  • rs1490813 (0.000514773)
  • rs922943 (0.000479007)
  • rs249904 (0.000376552)
  • rs8003056 (0.000412007)
  • rs2032563 (0.000401784)
  • rs9304496 (0.000988927)
  • rs7677714 (0.003657755)
  • rs723525 (0.001006991)
  • rs2201186 (0.000283386)
  • rs2553377 (0.000465537)
  • rs1076584 (0.000456922)
  • rs2232548 (0.008366096)
  • rs3816754 (0.000836276)
  • rs9324976 (0.001652411)
  • rs10229977 (0.001130238)
  • rs6991271 (0.000551626)
  • rs2738679 (0.000869114)
  • rs1812736 (0.002934594)
  • rs15606 (0.000563688)
  • rs7505612 (0.000286732)
  • rs1517598 (0.000445256)
  • rs524533 (0.000732713)
  • rs2660885 (0.002142566)
  • rs7319813 (0.000391694)
  • rs4541274 (0.000704007)
  • rs1033686 (0.002359037)
  • rs205499 (0.000424485)
  • rs3780223 (0.012546995)
  • rs9894254 (0.000864702)
  • rs7149754 (0.000599952)
  • rs1868778 (0.000449238)
  • rs4755936 (0.003578524)
  • rs8069437 (0.001957535)
  • rs1674159 (0.000520159)
  • rs11601702 (0.000433191)
  • rs2116538 (0.000443718)
  • rs9554632 (0.000603259)
  • rs975072 (0.000318229)
  • rs10210870 (0.001298236)
  • rs7013313 (0.00044704)
  • rs3817530 (0.000478367)
  • rs7318601 (0.000508958)
  • rs11218921 (0.001256827)
  • rs12737127 (0.002076359)
  • rs6580511 (0.000298278)
  • rs1411552 (0.000879392)
  • rs10489436 (0.000883064)
  • rs12960908 (0.000576108)
  • rs3803833 (0.000492924)
  • rs6732163 (0.000460236)
  • rs3019435 (0.001006354)
  • rs10890985 (0.000502038)
  • rs2745252 (0.00131503)
  • rs10509271 (0.002944036)
  • rs793017 (0.000595001)

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