Sikora, Frederieke Flachsbart, Lene Christiansen, Anton J.M. De Craen, Thomas

11 12 13,14 15 16 B.L. Kirkwood, Irene Maeve Rea, Michel Poulain, Jean-Marie Robine, Silvana Valensin,

17 18 19 20 Antonietta Stazi, Giuseppe Passarino, Luca Deiana, Efstathios S. Gonos, Lavinia

© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great

2 Netherlands Consortium for Healthy Ageing, Leiden, 2333 ZC, The Netherlands

4 The National Institute for Health and Welfare, THL, Helsinki, FI-00271, Finland

School of Public Health, Tampere, FI-33014, Finland

11 Institute for Ageing and Health, Newcastle University, UNEW, Newcastle, NE1 7RU, United

Queens University of Belfast, QUB, Belfast, BT7 1NN, Northern Ireland, United Kingdom

Catholic University of Louvain, UCL, Louvain-la-Neuve, B-1348, Belgium

INSERM, Health & Demography, CRLC, Montpellier, 34298, France

22 School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom

di Scienze Statistiche, Sapienza University of Rome, Rome, Italy

30 Max Planck Institute for Demographic Research, MPIDR, Rostock, Germany.

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*Correspondence: Marian Beekman, Molecular Epidemiology, Leiden University Medical

show linkage with longevity; chromosome 14q11.2 (LOD=3.47), chromosome 17q12-q22

estimated at approximately 25% in the general population (Skytthe et al., 2003) with increasing

with a mean sibship size of 2.1 (Table 1).

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

We calculated non-parametric linkage scores over the whole genome for the three

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

When we consider the genes in the 1-LOD drop intervals of the linkage analysis as candidate

No significant association (p-value <8.7 x 10-7) was observed at the loci at chromosome 14q11.2,

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Affected sibpair analysis is a powerful tool to map strong dominant as well as recessive gene

other functional variation and multiple cis-elements are found to influence both APOE and TOMM40

gender but also by genetic background.

Subjects for association analysis within linked regions

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Combined linkage and association at APOEε2ε3ε4 locus

To investigate whether the linkage identified can be explained by the APOEε2ε3ε4

The Competitive Research Funding of the Tampere University Hospital and Academy of Finland

Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) (Leiden);

Access to genotype data from the TwinsUK cohort was kindly provided by the Department of

Barzilai N, Gabriely I, Atzmon G, Suh Y, Rothenberg D, Bergman A (2010) Genetic studies

study of 1651 nonagenarians. Eur J Hum Genet 13, 1154-1158.

Beekman M, Blauw GJ, Houwing-Duistermaat JJ, Brandt BW, Westendorp RG, Slagboom PE

Callegaro A, van Houwelingen HC, Houwing-Duistermaat JJ (2009) Score test for age at onset

genetic linkage analysis in selected sibling pairs. Stat Med 28, 1913-1926.

Deelen J, Beekman M, Uh HW, Helmer Q, Kuningas M, Christiansen L, Kremer D, van der

linkage to chromosomes 6, 7, and 14 in the Amish. Ann Hum Genet 75, 516-528.

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanche H, Thomas G, Perls TT, Daly MJ,

in selected families: the Leiden Longevity Study. Stat Med 28, 140-151.

R, Martinussen T, Christiansen L, Jeune B, ndersen-Ranberg K, Vaupel JW,

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Kuningas M, Magi R, Westendorp RG, Slagboom PE, Remm M, van HD (2007) Haplotypes in

influencing survival in long-lived individuals. Mech Ageing Dev 132, 324-330.

Newman AB, Walter S, Lunetta KL, Garcia ME, Slagboom PE, Christensen K, Arnold AM,

N, Glazer NL, Gudnason V, Hofman A, Kaplan R, Karasik D, Kelly-Hayes M,

Paternoster L, Evans DM, Nohr EA, Holst C, Gaborieau V, Brennan P, Gjesing AP, Grarup N,

Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, Bogan H, Joyce E, Brewster S,

evidence for common Caucasian loci. PLoS Genet 3, e97-

approach: the Leiden Longevity Study. Eur J Hum Genet 14, 79-84.

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Skytthe A, Valensin S, Jeune B, Cevenini E, Balard F, Beekman M, Bezrukov V, Blanche H,

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Walter S, Atzmon G, Demerath EW, Garcia ME, Kaplan RC, Kumari M, Lunetta KL, Milaneschi

Karasik D, Kiel DP, Kocher T, Kuningas M, Launer LJ, Lohman KK, Lutsey PL,

2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great and Ireland

Table S2 Mean age and age range of GEHA nonagenarian sibling cases.

genomewidelinkageresults_geha_all_phys_gen_map.xls

2 Germany Kiel 90 4 0 0 94 92.8 12 53 2 Denmark Odense 384 45 5 0 434 92.3 50 215 2 The Netherlands Leiden 150 14 2 0 166 93.0 20 82 2 United Kingdom Newcastle 98 1 0 0 99 92.8 7 55 2 United Kingdom Belfast 52 4 1 0 57 92.9 4 40 2 Belgium Louvain 76 1 0 0 77 92.9 13 40 2 France Montpellier 238 27 3 1 269 93.3 30 157 3 Italy Bologna 178 23 6 1 208 93.4 14 126 3 Italy Rome 51 2 0 0 53 92.5 6 32 3 Italy Calabria 181 7 1 0 189 93.0 24 79 3 Italy Sassari 43 2 0 0 45 93.4 3 24 3 Greece Athens 92 3 0 0 95 92.9 57 15 Total 1934 162 19 3 2118 92.9 263 1145

14q11.2 17q12-q22 19p13.3- 19q13.11-q13.32 p13.11 1 1 1 1 interval 0-12 cM 68-95 cM 20-42 cM 58-85 cM

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