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3. Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank

Author

Codd, V, Denniff, M, Swinfield, C, Warner, SC, Papakonstantinou, M, Sheth, S, Nanus, DE, Budgeon, CA, Musicha, C, Bountziouka, V, Wang, Q, Bramley, R, Allara, E, Kaptoge, S, Stoma, S, Jiang, T, Butterworth, AS, Wood, AM, Di Angelantonio, E, Thompson, Danesh, JN, Nelson, CP, Samani, NJ, Codd, V [0000-0002-9430-8254], Papakonstantinou, M [0000-0003-2664-9046], Budgeon, CA [0000-0002-1910-5561], Allara, E [0000-0002-1634-8330], Butterworth, AS [0000-0002-6915-9015], Thompson, JR [0000-0003-4819-1611], Samani, NJ [0000-0002-3286-8133], and Apollo - University of Cambridge Repository

Subjects
Male, Aging, Neuroscience (miscellaneous), Infant, Newborn, Ethnicity, Leukocytes, Humans, Female, Geriatrics and Gerontology, Telomere, United Kingdom, Biological Specimen Banks
Abstract

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

Published
2022

4. Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects

Author

Topiwala, A, Taschler, B, Ebmeier, KP, Smith, S, Zhou, H, Levey, DF, Codd, V, Samani, NJ, Gelernter, J, Nichols, TE, Burgess, S, Topiwala, A [0000-0002-8408-0372], Taschler, B [0000-0001-6574-4789], Ebmeier, KP [0000-0002-5190-7038], Zhou, H [0000-0002-7694-6391], Levey, DF [0000-0001-8431-9569], Gelernter, J [0000-0002-4067-1859], Nichols, TE [0000-0002-4516-5103], Burgess, S [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Alcohol Drinking, Ethanol, Humans, Mendelian Randomization Analysis, Telomere, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Funder: UK Medical Research Council (G1001354 & MR/K013351/1) European Commission (Horizon 2020 732592), Funder: Wellcome Trust WIN, Funder: US Department of Veterans Affairs (I01CX001849), Funder: Li Ka Shing Centre for Health Information and Discovery Wellcome Trust 100309/Z/12/Z, Funder: National Institute for Health Research Cambridge Biomedical Research Centre Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z), Funder: Leicester Cardiovascular Biomedical Research Centre, Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.

Published
2022
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5. Investigation of a UK biobank cohort reveals causal associations of self-reported walking pace with telomere length

Author

Dempsey, PC, Musicha, C, Rowlands, AV, Davies, M, Khunti, K, Razieh, C, Timmins, I, Zaccardi, F, Codd, V, Nelson, CP, Yates, T, Samani, NJ, Dempsey, PC, Musicha, C, Rowlands, AV, Davies, M, Khunti, K, Razieh, C, Timmins, I, Zaccardi, F, Codd, V, Nelson, CP, Yates, T, and Samani, NJ

Abstract

Walking pace is a simple and functional form of movement and a strong predictor of health status, but the nature of its association with leucocyte telomere length (LTL) is unclear. Here we investigate whether walking pace is associated with LTL, which is causally associated with several chronic diseases and has been proposed as a marker of biological age. Analyses were conducted in 405,981 UK Biobank participants. We show that steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with accelerometer-assessed measures of physical activity further supporting this through an association between LTL and habitual activity intensity, but not with total amount of activity. Bi-directional mendelian randomisation analyses suggest a causal link between walking pace and LTL, but not the other way around. A faster walking pace may be causally associated with longer LTL, which could help explain some of the beneficial effects of brisk walking on health status. Given its simple measurement and low heritability, self-reported walking pace may be a pragmatic target for interventions.

Published
2022

7. Telomere length is independently associated with all-cause mortality in chronic heart failure

Author

Romaine, S.P.R. Denniff, M. Codd, V. Nath, M. Koekemoer, A. Anker, S.D. Cleland, J.G. Filippatos, G. Levin, D. Metra, M. Mordi, I.R. Ouwerkerk, W. Ter Maaten, J.M. Van Veldhuisen, D.J. Zannad, F. Ng, L.L. Van Der Harst, P. Lang, C.C. Voors, A.A. Nelson, C.P. Samani, N.J.

Abstract

Objective Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure. Methods We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation. Results In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10 -5), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10 -3). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10 -3). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855). Conclusion In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality. © Authors 2021

Published
2022

8. Response to the letter by Esteves et al.

Author

Send, T. S., Gilles, M., Codd, V., Wolf, I. A. C., Bardtke, S., Streit, F., Strohmaier, J., Frank, J., Schendel, D., Sütterlin, M. W., Denniff, M., Laucht, M., Samani, N. J., Deuschle, M., Rietschel, M., and Witt, S. H.

Published
2018
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9. Variation in Human Herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

Author

Wood, M.L., primary, Veal, C., additional, Neumann, R., additional, Suárez, N.M., additional, Nichols, J., additional, Parker, A.J., additional, Martin, D., additional, Romaine, S.P.R, additional, Codd, V., additional, Samani, N.J., additional, Voors, A.A., additional, Tomaszewski, M., additional, Flamand, L., additional, Davison, A.J., additional, and Royle, N.J., additional

Published
2021
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10. Longitudinal telomere length and body composition in healthy term-born infants during the first two years of life

Author

Fluiter, K.S. (Kirsten) de, Codd, V. (Veryan), Denniff, M. (Matthew), Kerkhof, G.F. (Gerthe), Beijsterveldt, I.A.L.P. (Inge) van, Breij, L. (Laura), Samani, N.J. (Nilesh), Abrahamse-Berkeveld, M. (Marieke), Hokken-Koelega, A.C.S. (Anita), Fluiter, K.S. (Kirsten) de, Codd, V. (Veryan), Denniff, M. (Matthew), Kerkhof, G.F. (Gerthe), Beijsterveldt, I.A.L.P. (Inge) van, Breij, L. (Laura), Samani, N.J. (Nilesh), Abrahamse-Berkeveld, M. (Marieke), and Hokken-Koelega, A.C.S. (Anita)

Abstract

Objective Leukocyte telomere length (LTL) is one of the markers of biological aging as shortening occurs over time. Shorter LTL has been associated with adiposity and a higher risk of cardiovascular diseases. The objective was to assess LTL and LTL shortening during the first 2 years of life in healthy, term-born infants and to associate LTL shortening with potential stressors and body composition. Study design In 145 healthy, term-born infants (85 boys), we measured LTL in blood, expressed as telomere to single-gene copy ratio (T/S ratio), at 3 months and 2 years by quantitative PCR technique. Fat mass (FM) was assessed longitudinally by PEAPOD, DXA, and abdominal FM by ultrasound. Results LTL decreased by 8.5% from 3 months to 2 years (T/S ratio 4.10 vs 3.75, p<0.001). LTL shortening from 3 months to 2 years associated with FM%(R = 0.254), FM index(R = 0.243) and visceral FM(R = 0.287) at 2 years. LTL shortening tended to associate with gain in FM% from 3 to 6 months (R = 0.155, p = 0.11), in the critical window for adiposity programming. There was a trend to a shorter LTL in boys at 2 years(p = 0.056). LTL shortening from 3 months to 2 years was not different between sexes. Conclusion We present longitudinal LTL values and show that LTL shortens considerably (8.5%) during the first 2 years of life. LTL shortening during first 2 years of life was associated with FM%, FMI and visceral FM at age 2 years, suggesting that adverse adiposity programming in early life could contribute to more LTL shortening.

Published
2021
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11. Longitudinal telomere length and body composition in healthy term-born infants during the first two years of life

Author

de Fluiter, Kirsten, Codd, V, Denniff, M, Kerkhof, Gerthe, van Beijsterveldt, Inge, Breij, Laura, Samani, NJ, Abrahamse-Berkeveld, M, Hokken - Koelega, Anita, de Fluiter, Kirsten, Codd, V, Denniff, M, Kerkhof, Gerthe, van Beijsterveldt, Inge, Breij, Laura, Samani, NJ, Abrahamse-Berkeveld, M, and Hokken - Koelega, Anita

Abstract

Objective Leukocyte telomere length (LTL) is one of the markers of biological aging as shortening occurs over time. Shorter LTL has been associated with adiposity and a higher risk of cardiovascular diseases. The objective was to assess LTL and LTL shortening during the first 2 years of life in healthy, term-born infants and to associate LTL shortening with potential stressors and body composition. Study design In 145 healthy, term-born infants (85 boys), we measured LTL in blood, expressed as telomere to single-gene copy ratio (T/S ratio), at 3 months and 2 years by quantitative PCR technique. Fat mass (FM) was assessed longitudinally by PEAPOD, DXA, and abdominal FM by ultrasound. Results LTL decreased by 8.5% from 3 months to 2 years (T/S ratio 4.10 vs 3.75, p<0.001). LTL shortening from 3 months to 2 years associated with FM%(R = 0.254), FM index(R = 0.243) and visceral FM(R = 0.287) at 2 years. LTL shortening tended to associate with gain in FM% from 3 to 6 months (R = 0.155, p = 0.11), in the critical window for adiposity programming. There was a trend to a shorter LTL in boys at 2 years(p = 0.056). LTL shortening from 3 months to 2 years was not different between sexes. Conclusion We present longitudinal LTL values and show that LTL shortens considerably (8.5%) during the first 2 years of life. LTL shortening during first 2 years of life was associated with FM%, FMI and visceral FM at age 2 years, suggesting that adverse adiposity programming in early life could contribute to more LTL shortening.

Published
2021

12. Telomere length loss due to smoking and metabolic traits

Author

Huzen, J., Wong, L. S. M., van Veldhuisen, D. J., Samani, N. J., Zwinderman, A. H., Codd, V., Cawthon, R. M., Benus, G. F. J. D., van der Horst, I. C.C., Navis, G., Bakker, S. J. L., Gansevoort, R. T., de Jong, P. E., Hillege, H. L., van Gilst, W. H., de Boer, R. A., and van der Harst, P.

Published
2014
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13. A major population resource of 474,074 participants in UK Biobank to investigate determinants and biomedical consequences of leukocyte telomere length

Author

Codd, V., primary, Denniff, M., additional, Swinfield, C., additional, Warner, S.C., additional, Papakonstantinou, M., additional, Sheth, S., additional, Nanus, D.E., additional, Budgeon, C.A., additional, Musicha, C., additional, Bountziouka, V., additional, Wang, Q., additional, Bramley, R., additional, Allara, E., additional, Kaptoge, S., additional, Stoma, S., additional, Jiang, T., additional, Butterworth, A.S., additional, Wood, A.M., additional, Di Angelantonio, E., additional, Thompson, J.R., additional, Danesh, J.N., additional, Nelson, C.P., additional, and Samani, N. J., additional

Published
2021
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14. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH

Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020

15. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH Study Group IBD Investigators Essen-Heidelberg Investigators AMFS Investigators MelaNostrum Consortium

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

16. Evidence for accelerated biological aging in young adults with prader-willi syndrome

Author

Donze, S.H., Codd, V. (Veryan), Damen, L. (Léonie), Goedegebuure, W.J., Denniff, M. (Matthew), Samani, N.J. (Nilesh), Velden, J.A.M. (Job) van der, Hokken-Koelega, A.C.S. (Anita), Donze, S.H., Codd, V. (Veryan), Damen, L. (Léonie), Goedegebuure, W.J., Denniff, M. (Matthew), Samani, N.J. (Nilesh), Velden, J.A.M. (Job) van der, and Hokken-Koelega, A.C.S. (Anita)

Abstract

Objective: Adults with Prader–Willi syndrome (PWS) are at increased risk of developing age-associated diseases early in life and, like in premature aging syndromes, aging might be accelerated. We investigated leukocyte telomere length (LTL), a marker of biological age, in young adults with PWS and compared LTL to healthy young adults of similar age. As all young adults with PWS were treated with growth hormone (GH), we also compared LTL in PWS subjects to GH-treated young adults born short for gestational age (SGA). Design: Cross-sectional study in age-matched young adults; 47 with PWS, 135 healthy, and 75 born SGA. Measurements: LTL measured by quantitative polymerase chain reaction, expressed as telomere/single copy gene ratio. Results: Median (interquartile range) LTL was 2.6 (2.4–2.8) at a median (interquartile range) age of 19.2 (17.7–21.3) years in PWS, 3.1 (2.9–3.5) in healthy young adults and 3.1 (2.8–3.4) in the SGA group. Median LTL in PWS was significantly lower compared to both control groups (P < .01). In PWS, a lower LTL tended to be associated with a lower total IQ (r = 0.35, P = .08). There was no association between LTL and duration of GH treatment, cumulative GH dose, or several risk factors for type 2 diabetes mellitus or cardiovascular disease. Conclusions: Young adults with PWS have significantly shorter median LTL compared to agematched healthy young adults and GH-treated young adults born SGA. The shorter telomeres might play a role in the premature aging in PWS, independent of GH. Longitudinal research is needed to determine the influence of LTL on aging in PWS.

Published
2020
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17. Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length

Author

Spek, A. (Ashley) van der, Warner, S.C. (Sophie C.), Broer, L. (Linda), Nelson, C.P. (Christopher), Vojinović, D. (Dina), Ahmad, S. (Shahzad), Arp, P.P. (Pascal), Brouwer, R.W.W. (Rutger), Denniff, M. (Matthew), van den hout, M.C.G.N. (Mirjam), Rooij, J.G.J. (Jeroen) van, Kraaij, R. (Robert), IJcken, W.F.J. (Wilfred) van, Samani, N.J. (Nilesh), Ikram, M.A. (Arfan), Uitterlinden, A.G. (André), Codd, V. (Veryan), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Spek, A. (Ashley) van der, Warner, S.C. (Sophie C.), Broer, L. (Linda), Nelson, C.P. (Christopher), Vojinović, D. (Dina), Ahmad, S. (Shahzad), Arp, P.P. (Pascal), Brouwer, R.W.W. (Rutger), Denniff, M. (Matthew), van den hout, M.C.G.N. (Mirjam), Rooij, J.G.J. (Jeroen) van, Kraaij, R. (Robert), IJcken, W.F.J. (Wilfred) van, Samani, N.J. (Nilesh), Ikram, M.A. (Arfan), Uitterlinden, A.G. (André), Codd, V. (Veryan), Amin, N. (Najaf), and Duijn, C.M. (Cornelia) van

Abstract

Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10–7, minor allele frequency of 0.2–0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10−6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10–4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

Published
2020
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18. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), Codd, V. (Veryan), Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), and Codd, V. (Veryan)

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Published
2020
Full Text
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19. Evidence for Accelerated Biological Aging in Young Adults with Prader-Willi Syndrome

Author

Donze, Stephany H., Codd, V., Damen, Layla, Goedegebuure, Wesley J., Denniff, Matthew, Samani, N.J., Velden, A.A.E.M. van der, Hokken-Koelega, Anita C.S., Donze, Stephany H., Codd, V., Damen, Layla, Goedegebuure, Wesley J., Denniff, Matthew, Samani, N.J., Velden, A.A.E.M. van der, and Hokken-Koelega, Anita C.S.

Abstract

Contains fulltext : 221496.pdf (Publisher’s version ) (Open Access)

Published
2020

20. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Alves, ADSC, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, A, Canzian, F, Hamby, SE, Hottenga, J-J, Jones, PD, Jousilahti, P, Magi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietilainen, KH, Salomaa, V, Sillanpaa, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, D, Chirlaque, M-D, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hagg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Ramon Quiros, J, Riitta Jarvelin, M, Rodriguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C, Codd, V, Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Alves, ADSC, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, A, Canzian, F, Hamby, SE, Hottenga, J-J, Jones, PD, Jousilahti, P, Magi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietilainen, KH, Salomaa, V, Sillanpaa, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, D, Chirlaque, M-D, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hagg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Ramon Quiros, J, Riitta Jarvelin, M, Rodriguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C, and Codd, V

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Published
2020

22. Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length

Author

van der Spek, Ashley, Warner, SC, Broer, Linda, Nelson, CP, Vojinovic, Dina, Ahmad, Shahzad, Arp, Pascal, Brouwer, Rutger, Denniff, M, Van den Hout - van Vroonhoven, Mirjam, van Rooij, Jeroen, Kraaij, Robert, van Ijcken, Wilfred, Samani, NJ, Ikram, Arfan, Uitterlinden, André, Codd, V, Amin, Najaf, Duijn, Cornelia, van der Spek, Ashley, Warner, SC, Broer, Linda, Nelson, CP, Vojinovic, Dina, Ahmad, Shahzad, Arp, Pascal, Brouwer, Rutger, Denniff, M, Van den Hout - van Vroonhoven, Mirjam, van Rooij, Jeroen, Kraaij, Robert, van Ijcken, Wilfred, Samani, NJ, Ikram, Arfan, Uitterlinden, André, Codd, V, Amin, Najaf, and Duijn, Cornelia

Published
2020

23. Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

Author

Spek, A. (Ashley) van der, Boer, L (Linda), Draisma, G. (Gerrit), Pool, R. (Reńe), Albrecht, E. (Eva), Beekman, M. (Marian), Mangino, M. (Massimo), Raag, M. (Mait), Nyholt, D.R. (Dale R.), Dharuri, H. (Harish), Codd, V. (Veryan), Amin, N (Najaf), de Geus, E.J.C. (Eco J. C.), Deelen, J. (Joris), Demirkan, A. (Ayşe), Yet, I. (Idil), Fischer, K. (Krista), Haller, T. (Toomas), Henders, A.K. (Anjali K.), Isaacs, A. (Aaron), Medland, S.E. (Sarah E.), Montgomery, G.W. (Grant W.), Mooijaart, S.P. (Simon), Strauch, K. (Konstantin), Suchiman, H.E.D. (H. Eka D.), Vaarhorst, A.A.M. (Anika), Heemst, D. (Diana) van, Wang-Sattler, R. (Rui), Whitfield, J. (John), Willemsen, G. (Gonneke), Wright, M.J. (Margaret J.), Martin, N.G. (Nicholas), Samani, N.J. (Nilesh J.), Metspalu, A. (Andres), Eline Slagboom, P. (P.), Spector, T.D. (Tim D.), Boomsma, D.I. (Dorret I.), Duijn, C.M. (Cornelia) van, Gieger, C. (Christian), Spek, A. (Ashley) van der, Boer, L (Linda), Draisma, G. (Gerrit), Pool, R. (Reńe), Albrecht, E. (Eva), Beekman, M. (Marian), Mangino, M. (Massimo), Raag, M. (Mait), Nyholt, D.R. (Dale R.), Dharuri, H. (Harish), Codd, V. (Veryan), Amin, N (Najaf), de Geus, E.J.C. (Eco J. C.), Deelen, J. (Joris), Demirkan, A. (Ayşe), Yet, I. (Idil), Fischer, K. (Krista), Haller, T. (Toomas), Henders, A.K. (Anjali K.), Isaacs, A. (Aaron), Medland, S.E. (Sarah E.), Montgomery, G.W. (Grant W.), Mooijaart, S.P. (Simon), Strauch, K. (Konstantin), Suchiman, H.E.D. (H. Eka D.), Vaarhorst, A.A.M. (Anika), Heemst, D. (Diana) van, Wang-Sattler, R. (Rui), Whitfield, J. (John), Willemsen, G. (Gonneke), Wright, M.J. (Margaret J.), Martin, N.G. (Nicholas), Samani, N.J. (Nilesh J.), Metspalu, A. (Andres), Eline Slagboom, P. (P.), Spector, T.D. (Tim D.), Boomsma, D.I. (Dorret I.), Duijn, C.M. (Cornelia) van, and Gieger, C. (Christian)

Abstract

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10−6), methionine (p-value = 9.2 × 10−5), tyrosine (p-value = 2.1 × 10−4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10−4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10−4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10−4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

Published
2019
Full Text
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24. Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

Author

van der Spek, Ashley, Broer, Linda, Draisma, HHM, Pool, R, Albrecht, E, Beekman, M, Mangino, M, Raag, M, Nyholt, DR, Dharuri, HK, Codd, V, Amin, Najaf, de Geus, EJC, Deelen, J, Demirkan, Ayse, Yet, I, Fischer, K, Haller, T, Henders, AK, Isaacs, A, Medland, SE, Montgomery, GW, Mooijaart, SP, Strauch, K, Suchiman, HED, Vaarhorst, AAM, van Heemst, D, Wang-Sattler, R, Whitfield, JB, Willemsen, G, Wright, MJ, Martin, NG, Samani, NJ, Metspalu, A, Slagboom, PE (Eline), Spector, TD, Boomsma, DI, Duijn, CM, Gieger, C, van der Spek, Ashley, Broer, Linda, Draisma, HHM, Pool, R, Albrecht, E, Beekman, M, Mangino, M, Raag, M, Nyholt, DR, Dharuri, HK, Codd, V, Amin, Najaf, de Geus, EJC, Deelen, J, Demirkan, Ayse, Yet, I, Fischer, K, Haller, T, Henders, AK, Isaacs, A, Medland, SE, Montgomery, GW, Mooijaart, SP, Strauch, K, Suchiman, HED, Vaarhorst, AAM, van Heemst, D, Wang-Sattler, R, Whitfield, JB, Willemsen, G, Wright, MJ, Martin, NG, Samani, NJ, Metspalu, A, Slagboom, PE (Eline), Spector, TD, Boomsma, DI, Duijn, CM, and Gieger, C

Published
2019

25. Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

Author

Hagg, S., Zhan, Y., Karlsson, R., Gerritsen, L., Ploner, A., van der Lee, S. J., Broer, L., Deelen, J., Marioni, R. E., Wong, A., Lundquist, Anders, Zhu, G., Hansell, N. K., Sillanpaa, E., Fedko, I. O., Amin, N. A., Beekman, M., de Craen, A. J. M., Degerman, Sofie, Harris, S. E., Kan, K-J, Martin-Ruiz, C. M., Montgomery, G. W., Adolfsson, Annelie N., Reynolds, C. A., Samani, N. J., Suchiman, H. E. D., Viljanen, A., von Zglinicki, T., Wright, M. J., Hottenga, J-J, Boomsma, D. I., Rantanen, T., Kaprio, J. A., Nyholt, D. R., Martin, N. G., Nyberg, Lars, Adolfsson, Rolf, Kuh, D., Starr, J. M., Deary, I. J., Slagboom, P. E., van Duijn, C. M., Codd, V., Pedersen, N. L., Hagg, S., Zhan, Y., Karlsson, R., Gerritsen, L., Ploner, A., van der Lee, S. J., Broer, L., Deelen, J., Marioni, R. E., Wong, A., Lundquist, Anders, Zhu, G., Hansell, N. K., Sillanpaa, E., Fedko, I. O., Amin, N. A., Beekman, M., de Craen, A. J. M., Degerman, Sofie, Harris, S. E., Kan, K-J, Martin-Ruiz, C. M., Montgomery, G. W., Adolfsson, Annelie N., Reynolds, C. A., Samani, N. J., Suchiman, H. E. D., Viljanen, A., von Zglinicki, T., Wright, M. J., Hottenga, J-J, Boomsma, D. I., Rantanen, T., Kaprio, J. A., Nyholt, D. R., Martin, N. G., Nyberg, Lars, Adolfsson, Rolf, Kuh, D., Starr, J. M., Deary, I. J., Slagboom, P. E., van Duijn, C. M., Codd, V., and Pedersen, N. L.

Abstract

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

Published
2017
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26. Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

Author

Hagg, S, Zhan, Y, Karlsson, R, Gerritsen, L, Ploner, A, van der Lee, Sven, Broer, Linda, Deelen, J, Marioni, RE, Wong, A, Lundquist, A, Zhu, G, Hansell, NK, Sillanpaa, E, Fedko, IO, Amin, Najaf, Beekman, M, de Craen, AJM, Degerman, S, Harris, SE, Kan, KJ, Martin-Ruiz, CM, Montgomery, GW, Adolfsson, AN, Reynolds, CA, Samani, NJ, Suchiman, HED, Viljanen, A, von Zglinicki, T, Wright, MJ, Hottenga, JJ, Boomsma, DI, Rantanen, T, Kaprio, JA, Nyholt, DR, Martin, NG, Nyberg, L, Adolfsson, R, Kuh, D, Starr, JM, Deary, IJ, Slagboom, PE (Eline), Duijn, Cornelia, Codd, V, Pedersen, NL, Hagg, S, Zhan, Y, Karlsson, R, Gerritsen, L, Ploner, A, van der Lee, Sven, Broer, Linda, Deelen, J, Marioni, RE, Wong, A, Lundquist, A, Zhu, G, Hansell, NK, Sillanpaa, E, Fedko, IO, Amin, Najaf, Beekman, M, de Craen, AJM, Degerman, S, Harris, SE, Kan, KJ, Martin-Ruiz, CM, Montgomery, GW, Adolfsson, AN, Reynolds, CA, Samani, NJ, Suchiman, HED, Viljanen, A, von Zglinicki, T, Wright, MJ, Hottenga, JJ, Boomsma, DI, Rantanen, T, Kaprio, JA, Nyholt, DR, Martin, NG, Nyberg, L, Adolfsson, R, Kuh, D, Starr, JM, Deary, IJ, Slagboom, PE (Eline), Duijn, Cornelia, Codd, V, and Pedersen, NL

Published
2017

28. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)

Subjects
Male, Cancer Research, Candidate gene, Epidemiology, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, GENETICS & HEREDITY, Genetics (clinical), Genetics, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Middle Aged, 3. Good health, CYP17A1, Genetic Epidemiology, Genome-wide association, Myocardial-infarction, Susceptibility loci, Risk, Atherosclerosis, Metanalysis, Lipoprotein, Medicine, Female, Life Sciences & Biomedicine, Research Article, Asian Continental Ancestry Group, Adult, SUSCEPTIBILITY LOCI, lcsh:QH426-470, European Continental Ancestry Group, Biology, Polymorphism, Single Nucleotide, coronary artery disease, genetics, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, Genetic variation, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Molecular Biology, Gene, METAANALYSIS, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Cardiovascular Disease Epidemiology, Alleles, 030304 developmental biology, Aged, 0604 Genetics, Science & Technology, Case-control study, Genetic Variation, Human Genetics, Odds ratio, large-scale gene analysis, lcsh:Genetics, LIPOPROTEIN, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Case-Control Studies, Genetics of Disease, IBC 50K CAD Consortium, Developmental Biology, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.

Published
2016

29. INHERITED VARIANTS NEAR TERC AND TERT ARE ASSOCIATED WITH LONGER TELOMERES AND INCREASED GLIOMA RISK: GENOME-WIDE ASSOCIATION RESULTS FROM THE UCSF ADULT GLIOMA STUDY AND THE ENGAGE CONSORTIUM TELOMERE GROUP

Author

Walsh, K, Codd, V, Smirnov, I, Rice, T, Decker, P, Hansen, H, Molinaro, A, Pekmezci, M, Tihan, T, Berger, M, Chang, S, Prados, M, Lachance, D, O'Neill, BP, van der Harst, P, Wiencke, J, Samani, N, Jenkins, R, Wrensch, M, and Grp, ENGAGECT

Subjects
Oncology and Carcinogenesis, Neurosciences, Oncology & Carcinogenesis
Published
2014

30. Reproducibility of telomere length assessment: an international collaborative study

Author

Cooper, Rachel, Martin-Ruiz, CM, Baird, D, Roger, L, Boukamp, P, Krunic, D, Cawthon, R, Dokter, MM, van, der Harst P, Bekaert, S, de, Meyer T, Roos, G, Svenson, U, Codd, V, Samani, NJ, McGlynn, L, Shiels, PG, Pooley, KA, Dunning, AM, Cooper, R, Wong, A, Kingston, A, and von, Zglinicki T

Abstract

Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63–0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant ( P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.

Published
2014

31. The transcriptional landscape of age in human peripheral blood

Author

Peters, MJ, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Göring, HHH, Fornage, M, Liu, Y, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Van Rooij, J, Stolk, L, Broer, L, Verbiest, MMPJ, Jhamai, M, Arp, P, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, C, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Völzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, McRae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE, Helmer, Q, Den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, Blangero, J, Peters, MJ, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Göring, HHH, Fornage, M, Liu, Y, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Van Rooij, J, Stolk, L, Broer, L, Verbiest, MMPJ, Jhamai, M, Arp, P, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, C, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Völzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, McRae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE, Helmer, Q, Den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, and Blangero, J

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

32. Leukocyte telomere length in young adults born preterm: Support for accelerated biological ageing

Author

Smeets, C.C.J. (Lin), Codd, V. (Veryan), Samani, N.J. (Nilesh), Hokken-Koelega, A.C.S. (Anita), Smeets, C.C.J. (Lin), Codd, V. (Veryan), Samani, N.J. (Nilesh), and Hokken-Koelega, A.C.S. (Anita)

Abstract

Background Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease. Objectives To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age. Methods W

Published
2015
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33. The transcriptional landscape of age in human peripheral blood

Author

Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), Singleton, A., Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), and Singleton, A.

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015
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35. The transcriptional landscape of age in human peripheral blood

Author

Peters, Marjolein, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Goring, HHH, Fornage, M, Liu, YM, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, van Rooij, J, Stolk, Lisette, Broer, Linda, Verbiest, Michael, Jhamai, M, Arp, Pascal, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, Cindy, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Voelzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, Mcrae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE (Eline), Helmer, Q, den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, Blangero, J, Meulenbelt, I, Ressler, KJ, Yang, Jiaqi, Franke, L, Kettunen, J, Visscher, PM, Neely, GG, Korstanje, R, Hanson, RL, Prokisch, H, Ferrucci, L, Esko, T, Teumer, A, van Meurs, Joyce, Andrew, D, Peters, Marjolein, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Goring, HHH, Fornage, M, Liu, YM, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, van Rooij, J, Stolk, Lisette, Broer, Linda, Verbiest, Michael, Jhamai, M, Arp, Pascal, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, Cindy, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Voelzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, Mcrae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE (Eline), Helmer, Q, den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, Blangero, J, Meulenbelt, I, Ressler, KJ, Yang, Jiaqi, Franke, L, Kettunen, J, Visscher, PM, Neely, GG, Korstanje, R, Hanson, RL, Prokisch, H, Ferrucci, L, Esko, T, Teumer, A, van Meurs, Joyce, and Andrew, D

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

36. The transcriptional landscape of age in human peripheral blood

Author

Peters, M., Joehanes, R., Pilling, L., Schurmann, C., Conneely, K., Powell, J., Reinmaa, E., Sutphin, G., Zhernakova, A., Schramm, K., Wilson, Y., Kobes, S., Tukiainen, T., Ramos, Y., Göring, H., Fornage, M., Liu, Y., Gharib, S., Stranger, B., De Jager, P., Aviv, A., Levy, D., Murabito, J., Munson, P., Huan, T., Hofman, A., Uitterlinden, A., Rivadeneira, F., Van Rooij, J., Stolk, L., Broer, L., Verbiest, M., Jhamai, M., Arp, P., Metspalu, A., Tserel, L., Milani, L., Samani, N., Peterson, P., Kasela, S., Codd, V., Peters, A., Ward-Caviness, C., Herder, C., Waldenberger, M., Roden, M., Singmann, P., Zeilinger, S., Illig, T., Homuth, G., Grabe, H., Völzke, H., Steil, L., Kocher, T., Murray, A., Melzer, D., Yaghootkar, H., Bandinelli, S., Moses, Eric, Kent, J., Curran, J., Johnson, M., Williams-Blangero, S., Westra, H., McRae, A., Smith, J., Kardia, S., Hovatta, I., Perola, M., Ripatti, S., Salomaa, V., Henders, A., Peters, M., Joehanes, R., Pilling, L., Schurmann, C., Conneely, K., Powell, J., Reinmaa, E., Sutphin, G., Zhernakova, A., Schramm, K., Wilson, Y., Kobes, S., Tukiainen, T., Ramos, Y., Göring, H., Fornage, M., Liu, Y., Gharib, S., Stranger, B., De Jager, P., Aviv, A., Levy, D., Murabito, J., Munson, P., Huan, T., Hofman, A., Uitterlinden, A., Rivadeneira, F., Van Rooij, J., Stolk, L., Broer, L., Verbiest, M., Jhamai, M., Arp, P., Metspalu, A., Tserel, L., Milani, L., Samani, N., Peterson, P., Kasela, S., Codd, V., Peters, A., Ward-Caviness, C., Herder, C., Waldenberger, M., Roden, M., Singmann, P., Zeilinger, S., Illig, T., Homuth, G., Grabe, H., Völzke, H., Steil, L., Kocher, T., Murray, A., Melzer, D., Yaghootkar, H., Bandinelli, S., Moses, Eric, Kent, J., Curran, J., Johnson, M., Williams-Blangero, S., Westra, H., McRae, A., Smith, J., Kardia, S., Hovatta, I., Perola, M., Ripatti, S., Salomaa, V., and Henders, A.

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age’ of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

37. Identification of seven loci affecting mean telomere length and their association with disease

Author

Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, Hottenga JJ, Fischer K, Esko T, Surakka I, Broer L, Nyholt DR, Mateo Leach I, Salo P, Hxe4gg S, Willemsen G, Perola M, Ouwehand W, Kaprio J, Martin NG, van Duijn CM, Hovatta I, Gieger C, Metspalu A, Boomsma DI, Jarvelin MR, Slagboom PE, Thompson JR, Spector TD, van der Harst P, and Samani NJ

Published
2013

38. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H. König, I.R. Kathiresan, S. Reilly, M.P. Assimes, T.L. Holm, H. Preuss, M. Stewart, A.F.R. Barbalic, M. Gieger, C. Absher, D. Aherrahrou, Z. Allayee, H. Altshuler, D. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Balmforth, A.J. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Boerwinkle, E. Braund, P.S. Brown, M.J. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Cichon, S. Codd, V. Davies, R.W. Dedoussis, G. Dehghan, A. Demissie, S. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. Mokhtari, N.E.E. Ellis, S.G. Elosua, R. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Folsom, A.R. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gudnason, V. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Hofman, A. Horne, B.D. Illig, T. Iribarren, C. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kaplan, L.M. Kastelein, J.J.P. Khaw, K.-T. Knowles, J.W. Kolovou, G. Kong, A. Laaksonen, R. Lambrechts, D. Leander, K. Lettre, G. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Meitinger, T. Melander, O. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peters, A. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Salomaa, V. Sampietro, M.L. Sandhu, M.S. Schadt, E. Scḧsignfer, A. Schillert, A. Schreiber, S. Schrezenmeir, J. Schwartz, S.M. Siscovick, D.S. Sivananthan, M. Sivapalaratnam, S. Smith, A. Smith, T.B. Snoep, J.D. Soranzo, N. Spertus, J.A. Stark, K. Stirrups, K. Stoll, M. Tang, W.H.W. Tennstedt, S. Thorgeirsson, G. Thorleifsson, G. Tomaszewski, M. Uitterlinden, A.G. Van Rij, A.M. Voight, B.F. Wareham, N.J. Wells, G.A. Wichmann, H.-E. Wild, P.S. Willenborg, C. Witteman, J.C.M. Wright, B.J. Ye, S. Zeller, T. Ziegler, A. Cambien, F. Goodall, A.H. Cupples, L.A. Quertermous, T. Mäsignrz, W. Hengstenberg, C. Blankenberg, S. Ouwehand, W.H. Hall, A.S. Deloukas, P. Thompson, J.R. Stefansson, K. Roberts, R. Thorsteinsdottir, U. O'Donnell, C.J. McPherson, R. Erdmann, J. Samani, N.J.

Subjects
cardiovascular diseases
Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. © 2011 Nature America, Inc. All rights reserved.

Published
2011

39. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

40. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

41. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H, König, Ir, Kathiresan, S, Reilly, Mp, Assimes, Tl, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Balmforth, Aj, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Boerwinkle, E, Braund, Ps, Brown, Mj, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, Mokhtari, Ne, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Kastelein, Jj, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Laaksonen, R, Lambrechts, D, Leander, K, Lettre, G, Li, M, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peters, A, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Soranzo, N, Spertus, Ja, Stark, K, Stirrups, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Thorleifsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Witteman, Jc, Wright, Bj, Ye, S, Zeller, T, Ziegler, A, Cambien, F, Goodall, Ah, Cupples, La, Quertermous, T, März, W, Hengstenberg, C, Blankenberg, S, Ouwehand, Wh, Hall, As, Deloukas, P, Thompson, Jr, Stefansson, K, Roberts, R, Thorsteinsdottir, U, O'Donnell, Cj, Mcpherson, R, Erdmann, J, the CARDIoGRAM Consortium, Samani, N. J., Epidemiology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine

Subjects
Adult, Male, Multifunction cardiogram, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Genetic determinism, artery disease, Article, Coronary artery disease, Gene Frequency, SDG 3 - Good Health and Well-being, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Allele, Genotyping, Allele frequency, coronary, Alleles, Genetics (clinical), Aged, Genetic association, business.industry, Case-control study, Middle Aged, medicine.disease, coronary artery disease, Large-scale association analysis, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

1. The CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics. 2011;43:333–338. ### Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants that are associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). The authors state that the current loci discovered in CAD and MI GWAS explain only a small fraction of the heritability of this complex disease. The authors hypothesized that a larger study would provide more power to discover common variants with modest effect sizes. Therefore, they formed the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium, which consisted of data from 14 GWAS of CAD and MI.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 14 GWAS of CAD comprising 22 233 cases and 64 762 control subjects, all of European ancestry. CAD was defined angiographically in a subset (n=7364) and by history in the entire sample. Presence of MI ranged from 48.1% to 100% of each cohort. After the meta-analysis, they genotyped the lead single-nucleotide polymorphisms (SNPs) within the most promising (defined a priori as P 90% power to detect effect sizes observed in the GWAS meta-analysis. Finally, to understand potential mechanisms and intermediate pathways by which novel loci may mediate risk, the authors interrogated 3 genome-wide studies that also assessed gene expression in multiple tissues, using human cell lines, a genome-wide map of allelic expression imbalance, and other human disease traits. ### Principal Findings The analysis of approximately 135 000 individuals more than doubled the number of loci with CAD association, yielding 13 previously unidentified loci and confirming at …

Published
2011

43. Telomere length in circulating leukocytes is associated with lung function and disease

Author

Albrecht, E, Sillanpaa, E, Karrasch, S, Alves, AC, Codd, V, Hovatta, I, Buxton, JL, Nelson, CP, Broer, Linda, Hagg, S, Mangino, M, Willemsen, G, Surakka, I, Ferreira, MAR, Amin, Najaf, Oostra, Ben, Backmand, HM, Peltonen, M, Sarna, S, Rantanen, T, Sipila, S, Korhonen, T, Madden, PAF, Gieger, C, Jorres, RA, Heinrich, J (Joachim), Behr, J, Huber, RM, Peters, A, Strauch, K, Wichmann, HE, Waldenberger, M, Blakemore, AIF, de Geus, EJC, Nyholt, DR, Henders, AK, Piirila, PL, Rissanen, A, Magnusson, PKE, Vinuela, A, Pietilainen, KH, Martin, NG, Pedersen, NL, Boomsma, DI, Spector, TD, Duijn, Cornelia, Kaprio, J, Samani, NJ, Jarvelin, MR, Schulz, H, Albrecht, E, Sillanpaa, E, Karrasch, S, Alves, AC, Codd, V, Hovatta, I, Buxton, JL, Nelson, CP, Broer, Linda, Hagg, S, Mangino, M, Willemsen, G, Surakka, I, Ferreira, MAR, Amin, Najaf, Oostra, Ben, Backmand, HM, Peltonen, M, Sarna, S, Rantanen, T, Sipila, S, Korhonen, T, Madden, PAF, Gieger, C, Jorres, RA, Heinrich, J (Joachim), Behr, J, Huber, RM, Peters, A, Strauch, K, Wichmann, HE, Waldenberger, M, Blakemore, AIF, de Geus, EJC, Nyholt, DR, Henders, AK, Piirila, PL, Rissanen, A, Magnusson, PKE, Vinuela, A, Pietilainen, KH, Martin, NG, Pedersen, NL, Boomsma, DI, Spector, TD, Duijn, Cornelia, Kaprio, J, Samani, NJ, Jarvelin, MR, and Schulz, H

Abstract

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

Published
2014

46. Meta-analysis of telomere length in 19713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Author

Broer, L., Codd, V., Nyholt, D.R., Deelen, J., Mangino, M., Willemsen, G., Albrecht, E., Amin, N., Beekman, M., Geus, E.J.C. de, Henders, A.K., Nelson, C.P., Steves, C.J., Wright, M.J., Craen, A.J.M. de, Isaacs, A., Matthews, M., Moayyeri, A., Montgomery, G.W., Oostra, B.A., Vink, J.M., Spector, T.D., Slagboom, P.E., Martin, N.G., Samani, N.J., Duijn, C.M. van, Boomsma, D.I., Broer, L., Codd, V., Nyholt, D.R., Deelen, J., Mangino, M., Willemsen, G., Albrecht, E., Amin, N., Beekman, M., Geus, E.J.C. de, Henders, A.K., Nelson, C.P., Steves, C.J., Wright, M.J., Craen, A.J.M. de, Isaacs, A., Matthews, M., Moayyeri, A., Montgomery, G.W., Oostra, B.A., Vink, J.M., Spector, T.D., Slagboom, P.E., Martin, N.G., Samani, N.J., Duijn, C.M. van, and Boomsma, D.I.

Abstract

Item does not contain fulltext, Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r = 0.42; P-value = 3.60 x 10(-61)) than father-offspring correlation (r = 0.33; P-value = 7.01 x 10(-5)), and a significant positive association with paternal age at offspring birth (beta = 0.005; P-value = 7.01 x 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r = 0.25; P-value = 2.82 x 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age >= 55 years; r = 0.31; P-value = 4.27 x 10(-23)) than in younger pairs (mean age <55 years; r = 0.20; P-value = 3.24 x 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.

Published
2013

47. Identification of seven loci affecting mean telomere length and their association with disease

Author

Codd, V., Nelson, C., Albrecht, E., Mangino, M., Deelen, J., Buxton, J., Hottenga, J., Fischer, K., Esko, T., Surakka, I., Broer, L., Nyholt, D., Leach, I., Salo, P., Hägg, S., Matthews, M., Palmen, J., Norata, Giuseppe, O'Reilly, P., Saleheen, D., Amin, N., Balmforth, A., Beekman, M., De Boer, R., Böhringer, S., Braund, P., Burton, P., Craen, A., Denniff, M., Dong, Y., Douroudis, K., Dubinina, E., Eriksson, J., Garlaschelli, K., Guo, D., Hartikainen, A., Henders, A., Houwing-Duistermaat, J., Kananen, L., Karssen, L., Kettunen, J., Klopp, N., Lagou, V., Van Leeuwen, E., Madden, P., Mägi, R., Magnusson, P., Männistö, S., McCarthy, M., Medland, S., Mihailov, E., Montgomery, G., Oostra, B., Palotie, A., Peters, A., Pollard, H., Pouta, A., Prokopenko, I., Ripatti, S., Salomaa, V., Suchiman, H., Valdes, A., Verweij, N., Viñuela, A., Wang, X., Wichmann, H., Widen, E., Willemsen, G., Wright, M., Xia, K., Xiao, X., Van Veldhuisen, D., Codd, V., Nelson, C., Albrecht, E., Mangino, M., Deelen, J., Buxton, J., Hottenga, J., Fischer, K., Esko, T., Surakka, I., Broer, L., Nyholt, D., Leach, I., Salo, P., Hägg, S., Matthews, M., Palmen, J., Norata, Giuseppe, O'Reilly, P., Saleheen, D., Amin, N., Balmforth, A., Beekman, M., De Boer, R., Böhringer, S., Braund, P., Burton, P., Craen, A., Denniff, M., Dong, Y., Douroudis, K., Dubinina, E., Eriksson, J., Garlaschelli, K., Guo, D., Hartikainen, A., Henders, A., Houwing-Duistermaat, J., Kananen, L., Karssen, L., Kettunen, J., Klopp, N., Lagou, V., Van Leeuwen, E., Madden, P., Mägi, R., Magnusson, P., Männistö, S., McCarthy, M., Medland, S., Mihailov, E., Montgomery, G., Oostra, B., Palotie, A., Peters, A., Pollard, H., Pouta, A., Prokopenko, I., Ripatti, S., Salomaa, V., Suchiman, H., Valdes, A., Verweij, N., Viñuela, A., Wang, X., Wichmann, H., Widen, E., Willemsen, G., Wright, M., Xia, K., Xiao, X., and Van Veldhuisen, D.

Abstract

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10 -8). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Published
2013

48. Telomere length in circulating leukocytes is associated with lung function and disease

Author

Albrecht, E., primary, Sillanpaa, E., additional, Karrasch, S., additional, Alves, A. C., additional, Codd, V., additional, Hovatta, I., additional, Buxton, J. L., additional, Nelson, C. P., additional, Broer, L., additional, Hagg, S., additional, Mangino, M., additional, Willemsen, G., additional, Surakka, I., additional, Ferreira, M. A. R., additional, Amin, N., additional, Oostra, B. A., additional, Backmand, H. M., additional, Peltonen, M., additional, Sarna, S., additional, Rantanen, T., additional, Sipila, S., additional, Korhonen, T., additional, Madden, P. A. F., additional, Gieger, C., additional, Jorres, R. A., additional, Heinrich, J., additional, Behr, J., additional, Huber, R. M., additional, Peters, A., additional, Strauch, K., additional, Wichmann, H. E., additional, Waldenberger, M., additional, Blakemore, A. I. F., additional, de Geus, E. J. C., additional, Nyholt, D. R., additional, Henders, A. K., additional, Piirila, P. L., additional, Rissanen, A., additional, Magnusson, P. K. E., additional, Vinuela, A., additional, Pietilainen, K. H., additional, Martin, N. G., additional, Pedersen, N. L., additional, Boomsma, D. I., additional, Spector, T. D., additional, van Duijn, C. M., additional, Kaprio, J., additional, Samani, N. J., additional, Jarvelin, M.-R., additional, and Schulz, H., additional

Published
2013
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49. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., Wallace, C., Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., and Wallace, C.

Abstract

Contains fulltext : 98050.pdf (publisher's version ) (Open Access), Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other approximately 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular f

Published
2011

50. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H. (Heribert), König, I.R. (Inke), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Assimes, T.L. (Themistocles), Holm, H. (Hilma), Preuss, M. (Michael), Stewart, A.F.R. (Alexandre), Barbalic, M. (maja), Gieger, C. (Christian), Absher, D. (Devin), Aherrahrou, Z. (Zouhair), Allayee, H. (Hooman), Altshuler, D. (David), Anand, S.S. (Sonia), Andersen, K.K. (Karl), Anderson, J.L. (Jeffrey), Ardissino, D. (Diego), Ball, S.G. (Stephen), Balmforth, A.J. (Anthony), Barnes, T.A. (Timothy), Becker, D.M. (Diane), Berger, K. (Klaus), Bis, J.C. (Joshua), Boekholdt, S.M. (Matthijs), Boerwinkle, E.A. (Eric), Braund, P.S. (Peter), Brown, M.J. (Morris), Burnett, M.S., Buysschaert, I. (Ian), Carlquist, J.F. (John), Chen, L. (Li), Cichon, S. (Sven), Codd, V. (Veryan), Davies, R.W. (Robert), Dedoussis, G.V. (George), Dehghan, A. (Abbas), Demissie, S. (Serkalem), Devaney, J. (Joseph), Diemert, P. (Patrick), Do, R. (Ron), Doering, A. (Angela), Eifert, S. (Sandra), Mokhtari, N.E.E., Ellis, S.G. (Stephen), Elosua, R. (Roberto), Engert, J.C. (James), Epstein, S.E. (Stephen), Faire, U. (Ulf) de, Fischer, M. (Marcus), Folsom, A.R. (Aaron), Freyer, J. (Jennifer), Gigante, B. (Bruna), Girelli, D. (Domenico), Gretarsdottir, S. (Solveig), Gudnason, V. (Vilmundur), Gulcher, J.R. (Jeffrey), Halperin, E. (Eran), Hammond, N. (Naomi), Hazen, S.L. (Stanley), Hofman, A. (Albert), Horne, B.D. (Benjamin), Illig, T. (Thomas), Iribarren, C. (Carlos), Jones, G.T. (Gregory), Jukema, J.W. (Jan Wouter), Kaiser, M.A. (Michael), Kaplan, R.C. (Robert), Khaw, K-T. (Kay-Tee), Knowles, J.W. (Joshua), Kolovou, G. (Genovefa), Kong, A. (Augustine), Laaksonen, R. (Reijo), Lambrechts, D. (Diether), Leander, K. (Karin), Lettre, G. (Guillaume), Lieb, W. (Wolfgang), Loley, C. (Christina), Lotery, A.J. (Andrew), Mannucci, P.M. (Pier), Maouche, S. (Seraya), Martinelli, N. (Nicola), McKeown, P.P. (Pascal), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Merlini, P.A., Mooser, V. (Vincent), Morgan, T. (Thomas), Mühleisen, T.W. (Thomas), Muhlestein, J.B. (Joseph), Münzel, T. (Thomas), Musunuru, K. (Kiran), Nahrstaedt, J. (Janja), Nelson, C.P. (Christopher P.), Nöthen, M.M. (Markus), Olivieri, O. (Oliviero), Patel, R.S. (Riyaz), Patterson, C.C. (Chris), Peters, A. (Annette), Peyvandi, F. (Flora), Qu, L. (Liming), Quyyumi, A.A. (Arshed), Rader, D.J. (Daniel), Rallidis, L.S. (Loukianos), Rice, C. (Catherine), Rosendaal, F.R. (Frits), Rubin, D. (Diana), Salomaa, V. (Veikko), Sampietro, M.L. (Maria Lourdes), Sandhu, M.S. (Manj), Schadt, E.E. (Eric), Schillert, A. (Arne), Schreiber, S. (Stefan), Schrezenmeir, J. (Jürgen), Schwartz, S.M. (Stephen), Siscovick, D.S. (David), Sivananthan, M. (Mohan), Sivapalaratnam, S. (Suthesh), Smith, A.V. (Albert Vernon), Snoep, J.D. (Jaapjan), Soranzo, N. (Nicole), Spertus, J.A. (John), Stark, K. (Klaus), Stirrups, K. (Kathy), Stoll, M. (Monika), Tang, W.H.W. (Wilson), Tennstedt, S. (Stephanie), Thorgeirsson, G. (Gudmundur), Thorleifsson, G. (Gudmar), Tomaszewski, M. (Maciej), Uitterlinden, A.G. (André), Rij, A.M. (Andre) van, Voight, B.F. (Benjamin), Wareham, N.J. (Nick), Wells, G.A. (George), Wichmann, H.E. (Heinz Erich), Wild, P.S. (Philipp), Willenborg, C. (Christina), Witteman, J.C.M. (Jacqueline), Wright, B.J. (Benjamin), Ye, S. (Shu), Zeller, T. (Tanja), Ziegler, A. (Andreas), Cambien, F. (François), Goodall, A.H. (Alison), Cupples, L.A. (Adrienne), Quertermous, T. (Thomas), Mäsignrz, W. (Winfried), Hengstenberg, C. (Christian), Blankenberg, S. (Stefan), Ouwehand, W.H. (Willem), Hall, A.S. (Alistair), Kastelein, J.J.P. (John), Deloukas, P. (Panagiotis), Thompson, J.R. (John), Stefansson, K. (Kari), Roberts, R. (Robert), Li, M. (Mingyao), Thorsteinsdottir, U. (Unnur), O'Donnell, C.J. (Christopher), McPherson, R. (Ruth), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), Schäffer, A. (Arne), Schunkert, H. (Heribert), König, I.R. (Inke), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Assimes, T.L. (Themistocles), Holm, H. (Hilma), Preuss, M. (Michael), Stewart, A.F.R. (Alexandre), Barbalic, M. (maja), Gieger, C. (Christian), Absher, D. (Devin), Aherrahrou, Z. (Zouhair), Allayee, H. (Hooman), Altshuler, D. (David), Anand, S.S. (Sonia), Andersen, K.K. (Karl), Anderson, J.L. (Jeffrey), Ardissino, D. (Diego), Ball, S.G. (Stephen), Balmforth, A.J. (Anthony), Barnes, T.A. (Timothy), Becker, D.M. (Diane), Berger, K. (Klaus), Bis, J.C. (Joshua), Boekholdt, S.M. (Matthijs), Boerwinkle, E.A. (Eric), Braund, P.S. (Peter), Brown, M.J. (Morris), Burnett, M.S., Buysschaert, I. (Ian), Carlquist, J.F. (John), Chen, L. (Li), Cichon, S. (Sven), Codd, V. (Veryan), Davies, R.W. (Robert), Dedoussis, G.V. (George), Dehghan, A. (Abbas), Demissie, S. (Serkalem), Devaney, J. (Joseph), Diemert, P. (Patrick), Do, R. (Ron), Doering, A. (Angela), Eifert, S. (Sandra), Mokhtari, N.E.E., Ellis, S.G. (Stephen), Elosua, R. (Roberto), Engert, J.C. (James), Epstein, S.E. (Stephen), Faire, U. (Ulf) de, Fischer, M. (Marcus), Folsom, A.R. (Aaron), Freyer, J. (Jennifer), Gigante, B. (Bruna), Girelli, D. (Domenico), Gretarsdottir, S. (Solveig), Gudnason, V. (Vilmundur), Gulcher, J.R. (Jeffrey), Halperin, E. (Eran), Hammond, N. (Naomi), Hazen, S.L. (Stanley), Hofman, A. (Albert), Horne, B.D. (Benjamin), Illig, T. (Thomas), Iribarren, C. (Carlos), Jones, G.T. (Gregory), Jukema, J.W. (Jan Wouter), Kaiser, M.A. (Michael), Kaplan, R.C. (Robert), Khaw, K-T. (Kay-Tee), Knowles, J.W. (Joshua), Kolovou, G. (Genovefa), Kong, A. (Augustine), Laaksonen, R. (Reijo), Lambrechts, D. (Diether), Leander, K. (Karin), Lettre, G. (Guillaume), Lieb, W. (Wolfgang), Loley, C. (Christina), Lotery, A.J. (Andrew), Mannucci, P.M. (Pier), Maouche, S. (Seraya), Martinelli, N. (Nicola), McKeown, P.P. (Pascal), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Merlini, P.A., Mooser, V. (Vincent), Morgan, T. (Thomas), Mühleisen, T.W. (Thomas), Muhlestein, J.B. (Joseph), Münzel, T. (Thomas), Musunuru, K. (Kiran), Nahrstaedt, J. (Janja), Nelson, C.P. (Christopher P.), Nöthen, M.M. (Markus), Olivieri, O. (Oliviero), Patel, R.S. (Riyaz), Patterson, C.C. (Chris), Peters, A. (Annette), Peyvandi, F. (Flora), Qu, L. (Liming), Quyyumi, A.A. (Arshed), Rader, D.J. (Daniel), Rallidis, L.S. (Loukianos), Rice, C. (Catherine), Rosendaal, F.R. (Frits), Rubin, D. (Diana), Salomaa, V. (Veikko), Sampietro, M.L. (Maria Lourdes), Sandhu, M.S. (Manj), Schadt, E.E. (Eric), Schillert, A. (Arne), Schreiber, S. (Stefan), Schrezenmeir, J. (Jürgen), Schwartz, S.M. (Stephen), Siscovick, D.S. (David), Sivananthan, M. (Mohan), Sivapalaratnam, S. (Suthesh), Smith, A.V. (Albert Vernon), Snoep, J.D. (Jaapjan), Soranzo, N. (Nicole), Spertus, J.A. (John), Stark, K. (Klaus), Stirrups, K. (Kathy), Stoll, M. (Monika), Tang, W.H.W. (Wilson), Tennstedt, S. (Stephanie), Thorgeirsson, G. (Gudmundur), Thorleifsson, G. (Gudmar), Tomaszewski, M. (Maciej), Uitterlinden, A.G. (André), Rij, A.M. (Andre) van, Voight, B.F. (Benjamin), Wareham, N.J. (Nick), Wells, G.A. (George), Wichmann, H.E. (Heinz Erich), Wild, P.S. (Philipp), Willenborg, C. (Christina), Witteman, J.C.M. (Jacqueline), Wright, B.J. (Benjamin), Ye, S. (Shu), Zeller, T. (Tanja), Ziegler, A. (Andreas), Cambien, F. (François), Goodall, A.H. (Alison), Cupples, L.A. (Adrienne), Quertermous, T. (Thomas), Mäsignrz, W. (Winfried), Hengstenberg, C. (Christian), Blankenberg, S. (Stefan), Ouwehand, W.H. (Willem), Hall, A.S. (Alistair), Kastelein, J.J.P. (John), Deloukas, P. (Panagiotis), Thompson, J.R. (John), Stefansson, K. (Kari), Roberts, R. (Robert), Li, M. (Mingyao), Thorsteinsdottir, U. (Unnur), O'Donnell, C.J. (Christopher), McPherson, R. (Ruth), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), and Schäffer, A. (Arne)

Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Published
2011
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