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7 results on '"Buxton, JL"'

1. 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

2. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Alves, AC, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bonnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M-A, Salerno, V, Clement, K, Claringbould, AAJ, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widen, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hypponen, E, Inskip, H, Kaplan, LM, Hedman, AK, Laara, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O'Sullivan, JM, Prokopenko, I, Herzig, K-H, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, Jarvelin, M-R, Alves, AC, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bonnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M-A, Salerno, V, Clement, K, Claringbould, AAJ, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widen, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hypponen, E, Inskip, H, Kaplan, LM, Hedman, AK, Laara, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O'Sullivan, JM, Prokopenko, I, Herzig, K-H, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, and Jarvelin, M-R

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

3. 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

4. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author

Paternoster, L, Standl, M, Chen, C-M, Ramasamy, A, Bonnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Saaf, A, Franke, A, Ellinghaus, D, Foelster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, A-L, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souef, P, St Pourcain, B, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, H-E, Mueller-Nurasyid, M, Novak, N, Klopp, N, Rodriguez, E, McArdle, W, Linneberg, A, Menne, T, Nohr, EA, Hofman, A, Uitterlinden, AG, van Duijin, CM, Rivadeneira, F, de Jongste, JC, van der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, J-J, Postma, D, Koppelman, GH, Smit, HA, Soderhall, C, Chawes, B, Kreiner-Moller, E, Bisgaard, H, Melen, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Jarvis, DL, Jaddoe, VWV, Gieger, C, Strachan, DP, Martin, NG, Jarvelin, M-R, Heinrich, J, Evans, DM, Weidinger, S, Paternoster, L, Standl, M, Chen, C-M, Ramasamy, A, Bonnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Saaf, A, Franke, A, Ellinghaus, D, Foelster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, A-L, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souef, P, St Pourcain, B, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, H-E, Mueller-Nurasyid, M, Novak, N, Klopp, N, Rodriguez, E, McArdle, W, Linneberg, A, Menne, T, Nohr, EA, Hofman, A, Uitterlinden, AG, van Duijin, CM, Rivadeneira, F, de Jongste, JC, van der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, J-J, Postma, D, Koppelman, GH, Smit, HA, Soderhall, C, Chawes, B, Kreiner-Moller, E, Bisgaard, H, Melen, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Jarvis, DL, Jaddoe, VWV, Gieger, C, Strachan, DP, Martin, NG, Jarvelin, M-R, Heinrich, J, Evans, DM, and Weidinger, S

Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Published
2012

5. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author

Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, and Melbye, M

Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Published
2012

6. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author

Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, and Melbye, M

Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Published
2012

7. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Walters, RG, Jacquemont, S, Valsesia, A, de Smith, AJ, Martinet, D, Andersson, J, Falchi, M, Chen, F, Andrieux, J, Lobbens, S, Delobel, B, Stutzmann, F, Moustafa, JSE-S, Chevre, J-C, Lecoeur, C, Vatin, V, Bouquillon, S, Buxton, JL, Boute, O, Holder-Espinasse, M, Cuisset, J-M, Lemaitre, M-P, Ambresin, A-E, Brioschi, A, Gaillard, M, Giusti, V, Fellmann, F, Ferrarini, A, Hadjikhani, N, Campion, D, Guilmatre, A, Goldenberg, A, Calmels, N, Mandel, J-L, Le Caignec, C, David, A, Isidor, B, Cordier, M-P, Dupuis-Girod, S, Labalme, A, Sanlaville, D, Beri-Dexheimer, M, Jonveaux, P, Leheup, B, Ounap, K, Bochukova, EG, Henning, E, Keogh, J, Ellis, RJ, MacDermot, KD, van Haelst, MM, Vincent-Delorme, C, Plessis, G, Touraine, R, Philippe, A, Malan, V, Mathieu-Dramard, M, Chiesa, J, Blaumeiser, B, Kooy, RF, Caiazzo, R, Pigeyre, M, Balkau, B, Sladek, R, Bergmann, S, Mooser, V, Waterworth, D, Reymond, A, Vollenweider, P, Waeber, G, Kurg, A, Palta, P, Esko, T, Metspalu, A, Nelis, M, Elliott, P, Hartikainen, A-L, McCarthy, MI, Peltonen, L, Carlsson, L, Jacobson, P, Sjostrom, L, Huang, N, Hurles, ME, O'Rahilly, S, Farooqi, IS, Maennik, K, Jarvelin, M-R, Pattou, F, Meyre, D, Walley, AJ, Coin, LJM, Blakemore, AIF, Froguel, P, Beckmann, JS, Walters, RG, Jacquemont, S, Valsesia, A, de Smith, AJ, Martinet, D, Andersson, J, Falchi, M, Chen, F, Andrieux, J, Lobbens, S, Delobel, B, Stutzmann, F, Moustafa, JSE-S, Chevre, J-C, Lecoeur, C, Vatin, V, Bouquillon, S, Buxton, JL, Boute, O, Holder-Espinasse, M, Cuisset, J-M, Lemaitre, M-P, Ambresin, A-E, Brioschi, A, Gaillard, M, Giusti, V, Fellmann, F, Ferrarini, A, Hadjikhani, N, Campion, D, Guilmatre, A, Goldenberg, A, Calmels, N, Mandel, J-L, Le Caignec, C, David, A, Isidor, B, Cordier, M-P, Dupuis-Girod, S, Labalme, A, Sanlaville, D, Beri-Dexheimer, M, Jonveaux, P, Leheup, B, Ounap, K, Bochukova, EG, Henning, E, Keogh, J, Ellis, RJ, MacDermot, KD, van Haelst, MM, Vincent-Delorme, C, Plessis, G, Touraine, R, Philippe, A, Malan, V, Mathieu-Dramard, M, Chiesa, J, Blaumeiser, B, Kooy, RF, Caiazzo, R, Pigeyre, M, Balkau, B, Sladek, R, Bergmann, S, Mooser, V, Waterworth, D, Reymond, A, Vollenweider, P, Waeber, G, Kurg, A, Palta, P, Esko, T, Metspalu, A, Nelis, M, Elliott, P, Hartikainen, A-L, McCarthy, MI, Peltonen, L, Carlsson, L, Jacobson, P, Sjostrom, L, Huang, N, Hurles, ME, O'Rahilly, S, Farooqi, IS, Maennik, K, Jarvelin, M-R, Pattou, F, Meyre, D, Walley, AJ, Coin, LJM, Blakemore, AIF, Froguel, P, and Beckmann, JS

Abstract

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Published
2010

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