title: High-density genomewide linkage analysis of exceptional human longevity identifies multiple novel loci.
abstract: BACKGROUND
  Human lifespan is approximately 25% heritable, and genetic factors may be particularly important for achieving exceptional longevity. Accordingly, siblings of centenarians have a dramatically higher probability of reaching extreme old age than the general population.
  
  
  RESULTS
  To map the loci conferring a survival advantage, we performed the second genomewide linkage scan on human longevity and the first using a high-density marker panel of single nucleotide polymorphisms. By systematically testing a range of minimum age cutoffs in 279 families with multiple long-lived siblings, we identified a locus on chromosome 3p24-22 with a genomewide significant allele-sharing LOD score of 4.02 (empirical P = 0.037) and a locus on chromosome 9q31-34 with a highly suggestive LOD score of 3.89 (empirical P = 0.054). The empirical P value for the combined result was 0.002. A third novel locus with a LOD score of 4.05 on chromosome 12q24 was detected in a subset of the data, and we also obtained modest evidence for a previously reported interval on chromosome 4q22-25.
  
  
  CONCLUSIONS
  Our linkage data should facilitate the discovery of both common and rare variants that determine genetic variability in lifespan.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Boyden
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
mesh_terms: D000369:Aged, 80 and over; D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008136:Longevity / Q000235:genetics*; D008297:Male
references.citation: Lancet. 1994 Feb 5;343(8893):327-9
references.pmid: 7905146
references.citation: Hum Mol Genet. 2004 Sep 1;13(17):1943-9
references.pmid: 15238506
references.citation: N Engl J Med. 1980 Jul 17;303(3):130-5
references.pmid: 7383070
references.citation: Am J Hum Genet. 1996 Jun;58(6):1347-63
references.pmid: 8651312
references.citation: Am J Hum Genet. 2005 Nov;77(5):754-67
references.pmid: 16252236
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8442-7
references.pmid: 12060785
references.citation: Am J Hum Genet. 2003 Feb;72(2):498-9
references.pmid: 12596795
references.citation: J Gerontol A Biol Sci Med Sci. 2007 Feb;62(2):202-5
references.pmid: 17339647
references.citation: Nature. 2008 Jan 31;451(7178):583-6
references.pmid: 18235501
references.citation: Am J Hum Genet. 1978 May;30(3):308-21
references.pmid: 677128
references.citation: Am J Hum Genet. 2004 Jun;74(6):1294-302
references.pmid: 15124101
references.citation: J Biol Chem. 1999 Dec 31;274(53):37795-9
references.pmid: 10608841
references.citation: Am Stat. 1985 Aug;39(3):176-85
references.pmid: 12267300
references.citation: Hum Hered. 2005;59(4):220-7
references.pmid: 16093727
references.citation: EMBO J. 2008 May 21;27(10):1513-24
references.pmid: 18418389
references.citation: Nature. 2003 Sep 11;425(6954):191-6
references.pmid: 12939617
references.citation: Science. 1998 May 8;280(5365):855-60
references.pmid: 9599158
references.citation: Am J Hum Genet. 1990 Feb;46(2):229-41
references.pmid: 2301393
references.citation: Am J Hum Genet. 1992 Sep;51(3):673-5
references.pmid: 1496996
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15998-6003
references.pmid: 15520384
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14115-20
references.pmid: 14615589
references.citation: Eur J Hum Genet. 2007 Mar;15(3):294-301
references.pmid: 17245409
references.citation: Circulation. 1991 Oct;84(4):1516-23
references.pmid: 1914093
references.citation: Trends Genet. 2001 May;17(5):233-5
references.pmid: 11335017
references.citation: Hum Genet. 1984;65(3):237-41
references.pmid: 6698548
references.citation: J Agric Food Chem. 2005 Apr 6;53(7):2489-98
references.pmid: 15796584
references.citation: J Gerontol A Biol Sci Med Sci. 2004 Mar;59(3):218-26
references.pmid: 15031305
references.citation: Hum Genet. 2006 Apr;119(3):312-21
references.pmid: 16463022
references.citation: Biochem Biophys Res Commun. 1998 Dec 30;253(3):667-71
references.pmid: 9918785
references.citation: Am J Hum Genet. 1995 May;56(5):1212-23
references.pmid: 7726179
references.citation: Annu Rev Pathol. 2010;5:253-95
references.pmid: 20078221
references.citation: Eur J Hum Genet. 2000 Oct;8(10):743-9
references.pmid: 11039573
references.citation: Science. 2004 Jul 16;305(5682):390-2
references.pmid: 15205477
references.citation: Am J Hum Genet. 2002 Aug;71(2):439-41
references.pmid: 12111669
references.citation: Am J Hum Genet. 1997 Nov;61(5):1179-88
references.pmid: 9345087
references.citation: Ann N Y Acad Sci. 2007 Apr;1100:21-45
references.pmid: 17460163
references.citation: J Clin Immunol. 2009 Jul;29(4):406-15
references.pmid: 19459036
references.citation: Cell. 1995 Nov 17;83(4):655-66
references.pmid: 7585968
references.citation: Cancer Res. 2009 May 15;69(10):4101-6
references.pmid: 19435923
references.citation: Am J Hum Genet. 2008 Jun;82(6):1375-84
references.pmid: 18513678
references.citation: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S13
references.pmid: 17903295
references.citation: Ageing Res Rev. 2006 Nov;5(4):371-87
references.pmid: 16337437
references.citation: Science. 2000 Sep 22;289(5487):2126-8
references.pmid: 11000115
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2700-5
references.pmid: 19196970
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10505-8
references.pmid: 11526246
references.citation: Annu Rev Biochem. 2008;77:727-54
references.pmid: 18373439
references.citation: Nat Genet. 1994 Jan;6(1):29-32
references.pmid: 8136829
references.citation: Am J Hum Genet. 2004 May;74(5):886-97
references.pmid: 15060841
references.citation: Mech Ageing Dev. 2000 Oct 20;119(1-2):25-39
references.pmid: 11040399
references.citation: Am J Hum Genet. 1990 Feb;46(2):242-53
references.pmid: 2301394
references.citation: Eur J Hum Genet. 2005 Oct;13(10):1154-8
references.pmid: 16015282
references.citation: J Gerontol A Biol Sci Med Sci. 2006 Apr;61(4):355-62
references.pmid: 16611701
references.citation: Genet Epidemiol. 2004 Apr;26(3):245-53
references.pmid: 15022210
references.citation: Am J Hum Genet. 1993 Feb;52(2):362-74
references.pmid: 8430697
references.citation: Int J Epidemiol. 2004 Oct;33(5):962-70
references.pmid: 15319409
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: PLoS Genet. 2007 Jul;3(7):e125
references.pmid: 17677003
references.citation: PLoS One. 2007 Oct 17;2(10):e1051
references.pmid: 17940615
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92
references.pmid: 18765803
references.citation: Genes Dev. 1999 Oct 1;13(19):2570-80
references.pmid: 10521401
references.citation: Proc Natl Acad Sci U S A. 2005 May 31;102(22):7906-9
references.pmid: 15911777
references.citation: Science. 1996 Sep 13;273(5281):1516-7
references.pmid: 8801636
references.citation: Nature. 2006 Nov 16;444(7117):337-42
references.pmid: 17086191
references.citation: Lancet. 1999 Aug 21;354(9179):652
references.pmid: 10466675
references.citation: Nat Rev Genet. 2006 Jun;7(6):436-48
references.pmid: 16708071
references.citation: J Am Geriatr Soc. 2002 Sep;50(9):1561-5
references.pmid: 12383155
references.citation: Nat Genet. 1995 Nov;11(3):241-7
references.pmid: 7581446
references.citation: Science. 2004 Dec 17;306(5704):2105-8
references.pmid: 15604409
references.citation: Aging Cell. 2009 Aug;8(4):460-72
references.pmid: 19489743
references.citation: Trans Am Clin Climatol Assoc. 1988;99:100-10
references.pmid: 3503432
references.citation: Genet Epidemiol. 2000 Oct;19(3):202-10
references.pmid: 11015124
references.citation: Am J Hum Genet. 2006 Feb;78(2):243-52
references.pmid: 16400608
references.citation: J Am Geriatr Soc. 2005 Jun;53(6):935-42
references.pmid: 15935014
references.citation: J Electrocardiol. 1986 Jul;19(3):203-11
references.pmid: 3746147
references.citation: Circ Cardiovasc Genet. 2008 Dec;1(2):93-9
references.pmid: 20031550
references.citation: Demography. 1979 Aug;16(3):439-54
references.pmid: 510638
references.citation: Am J Hum Genet. 2003 Feb;72(2):496-8
references.pmid: 12596794
references.citation: J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):B130-9
references.pmid: 11253150
references.citation: J Biol Chem. 2000 Mar 31;275(13):9636-44
references.pmid: 10734115
references.citation: J Gerontol A Biol Sci Med Sci. 2004 Mar;59(3):227-32
references.pmid: 15031306
references.citation: Hum Hered. 2005;60(3):134-42
references.pmid: 16319490
references.citation: Science. 1996 Apr 12;272(5259):258-62
references.pmid: 8602509
references.citation: Rejuvenation Res. 2009 Apr;12(2):95-104
references.pmid: 19415983
references.citation: Nature. 2001 Mar 8;410(6825):227-30
references.pmid: 11242085
references.citation: Nature. 2003 Feb 6;421(6923):634-9
references.pmid: 12571597
references.citation: Hum Mol Genet. 2009 Dec 15;18(24):4897-904
references.pmid: 19793722
references.citation: JAMA. 2004 Nov 17;292(19):2339-40
references.pmid: 15547160
references.citation: Nat Genet. 1997 Sep;17(1):21-4
references.pmid: 9288093
references.citation: Biogerontology. 2008 Apr;9(2):85-92
references.pmid: 18034366
references.citation: Am J Hum Genet. 2003 Feb;72(2):496
references.pmid: 12596792
references.citation: Cell Cycle. 2008 Apr 15;7(8):1020-35
references.pmid: 18414053
references.citation: Am J Med. 2004 Dec 1;117(11):851-60
references.pmid: 15589490
references.citation: Mech Ageing Dev. 2007 May-Jun;128(5-6):409-11
references.pmid: 17493663