22 results on '"Surakka, I."'
Number of results to display per page
Search Results
2. Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
- Author
-
Roychowdhury T, Klarin D, Levin MG, Spin JM, Rhee YH, Deng A, Headley CA, Tsao NL, Gellatly C, Zuber V, Shen F, Hornsby WE, Laursen IH, Verma SS, Locke AE, Einarsson G, Thorleifsson G, Graham SE, Dikilitas O, Pattee JW, Judy RL, Pauls-Verges F, Nielsen JB, Wolford BN, Brumpton BM, Dilmé J, Peypoch O, Juscafresa LC, Edwards TL, Li D, Banasik K, Brunak S, Jacobsen RL, Garcia-Barrio MT, Zhang J, Rasmussen LM, Lee R, Handa A, Wanhainen A, Mani K, Lindholt JS, Obel LM, Strauss E, Oszkinis G, Nelson CP, Saxby KL, van Herwaarden JA, van der Laan SW, van Setten J, Camacho M, Davis FM, Wasikowski R, Tsoi LC, Gudjonsson JE, Eliason JL, Coleman DM, Henke PK, Ganesh SK, Chen YE, Guan W, Pankow JS, Pankratz N, Pedersen OB, Erikstrup C, Tang W, Hveem K, Gudbjartsson D, Gretarsdottir S, Thorsteinsdottir U, Holm H, Stefansson K, Ferreira MA, Baras A, Kullo IJ, Ritchie MD, Christensen AH, Iversen KK, Eldrup N, Sillesen H, Ostrowski SR, Bundgaard H, Ullum H, Burgess S, Gill D, Gallagher K, Sabater-Lleal M, Surakka I, Jones GT, Bown MJ, Tsao PS, Willer CJ, and Damrauer SM
- Subjects
- Humans, Animals, Mice, Proprotein Convertase 9 genetics, Proprotein Convertase 9 metabolism, Subtilisin, Proprotein Convertases, Genome-Wide Association Study, Aortic Aneurysm, Abdominal genetics
- Abstract
Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2023
- Full Text
- View/download PDF
3. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- Author
-
Beaumont RN, Flatley C, Vaudel M, Wu X, Chen J, Moen GH, Skotte L, Helgeland Ø, Solé-Navais P, Banasik K, Albiñana C, Ronkainen J, Fadista J, Stinson SE, Trajanoska K, Wang CA, Westergaard D, Srinivasan S, Sánchez-Soriano C, Bilbao JR, Allard C, Groleau M, Kuulasmaa T, Leirer DJ, White F, Jacques PÉ, Cheng H, Hao K, Andreassen OA, Åsvold BO, Atalay M, Bhatta L, Bouchard L, Brumpton BM, Brunak S, Bybjerg-Grauholm J, Ebbing C, Elliott P, Engelbrechtsen L, Erikstrup C, Estarlich M, Franks S, Gaillard R, Geller F, Grove J, Hougaard DM, Kajantie E, Morgen CS, Nohr EA, Nyegaard M, Palmer CNA, Pedersen OB, Rivadeneira F, Sebert S, Shields BM, Stoltenberg C, Surakka I, Thørner LW, Ullum H, Vaarasmaki M, Vilhjalmsson BJ, Willer CJ, Lakka TA, Gybel-Brask D, Bustamante M, Hansen T, Pearson ER, Reynolds RM, Ostrowski SR, Pennell CE, Jaddoe VWV, Felix JF, Hattersley AT, Melbye M, Lawlor DA, Hveem K, Werge T, Nielsen HS, Magnus P, Evans DM, Jacobsson B, Järvelin MR, Zhang G, Hivert MF, Johansson S, Freathy RM, Feenstra B, and Njølstad PR
- Subjects
- Female, Humans, Pregnancy, Birth Weight genetics, Fetal Development genetics, Insulin, Male, Genome-Wide Association Study, Placenta metabolism
- Abstract
A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
4. Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.
- Author
-
Klarin D, Devineni P, Sendamarai AK, Angueira AR, Graham SE, Shen YH, Levin MG, Pirruccello JP, Surakka I, Karnam PR, Roychowdhury T, Li Y, Wang M, Aragam KG, Paruchuri K, Zuber V, Shakt GE, Tsao NL, Judy RL, Vy HMT, Verma SS, Rader DJ, Do R, Bavaria JE, Nadkarni GN, Ritchie MD, Burgess S, Guo DC, Ellinor PT, LeMaire SA, Milewicz DM, Willer CJ, Natarajan P, Tsao PS, Pyarajan S, and Damrauer SM
- Subjects
- Humans, Genome-Wide Association Study, Pedigree, Veterans, Aortic Aneurysm, Thoracic genetics, Aortic Dissection genetics
- Abstract
The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2023
- Full Text
- View/download PDF
5. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.
- Author
-
Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, Weeks EM, Wang M, Hindy G, Zhou W, Grace C, Roselli C, Marston NA, Kamanu FK, Surakka I, Venegas LM, Sherliker P, Koyama S, Ishigaki K, Åsvold BO, Brown MR, Brumpton B, de Vries PS, Giannakopoulou O, Giardoglou P, Gudbjartsson DF, Güldener U, Haider SMI, Helgadottir A, Ibrahim M, Kastrati A, Kessler T, Kyriakou T, Konopka T, Li L, Ma L, Meitinger T, Mucha S, Munz M, Murgia F, Nielsen JB, Nöthen MM, Pang S, Reinberger T, Schnitzler G, Smedley D, Thorleifsson G, von Scheidt M, Ulirsch JC, Arnar DO, Burtt NP, Costanzo MC, Flannick J, Ito K, Jang DK, Kamatani Y, Khera AV, Komuro I, Kullo IJ, Lotta LA, Nelson CP, Roberts R, Thorgeirsson G, Thorsteinsdottir U, Webb TR, Baras A, Björkegren JLM, Boerwinkle E, Dedoussis G, Holm H, Hveem K, Melander O, Morrison AC, Orho-Melander M, Rallidis LS, Ruusalepp A, Sabatine MS, Stefansson K, Zalloua P, Ellinor PT, Farrall M, Danesh J, Ruff CT, Finucane HK, Hopewell JC, Clarke R, Gupta RM, Erdmann J, Samani NJ, Schunkert H, Watkins H, Willer CJ, Deloukas P, Kathiresan S, and Butterworth AS
- Subjects
- Humans, Genome-Wide Association Study, Coronary Artery Disease genetics
- Abstract
The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
6. Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.
- Author
-
Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li X, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtimäki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen Z, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li L, Lin K, Lind L, Locantore N, Luan J, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao D, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Artigas MS, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, Kähönen M, Polašek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, and Wain LV
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2019
- Full Text
- View/download PDF
7. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.
- Author
-
Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li X, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtimäki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen Z, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li L, Lin K, Lind L, Locantore N, Luan J, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao D, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Soler Artigas M, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, Kähönen M, Polašek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, and Wain LV
- Subjects
- Aged, Aged, 80 and over, Case-Control Studies, Female, Genome-Wide Association Study methods, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Risk Factors, Smoking genetics, Genetic Predisposition to Disease genetics, Lung physiopathology, Pulmonary Disease, Chronic Obstructive genetics
- Abstract
Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
- Published
- 2019
- Full Text
- View/download PDF
8. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.
- Author
-
Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham SE, Herron TJ, McCarthy S, Schmidt EM, Sveinbjornsson G, Surakka I, Mathis MR, Yamazaki M, Crawford RD, Gabrielsen ME, Skogholt AH, Holmen OL, Lin M, Wolford BN, Dey R, Dalen H, Sulem P, Chung JH, Backman JD, Arnar DO, Thorsteinsdottir U, Baras A, O'Dushlaine C, Holst AG, Wen X, Hornsby W, Dewey FE, Boehnke M, Kheterpal S, Mukherjee B, Lee S, Kang HM, Holm H, Kitzman J, Shavit JA, Jalife J, Brummett CM, Teslovich TM, Carey DJ, Gudbjartsson DF, Stefansson K, Abecasis GR, Hveem K, and Willer CJ
- Subjects
- Biological Specimen Banks, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Genomics methods, Heart Defects, Congenital genetics, Humans, Risk, Atrial Fibrillation genetics, Mutation genetics
- Abstract
To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)
1 , or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy'2 , either during fetal heart development or as a response to stress in the adult heart.- Published
- 2018
- Full Text
- View/download PDF
9. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
- Author
-
Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, Obeidat M, Henry AP, Portelli MA, Hall RJ, Billington CK, Rimington TL, Fenech AG, John C, Blake T, Jackson VE, Allen RJ, Prins BP, Campbell A, Porteous DJ, Jarvelin MR, Wielscher M, James AL, Hui J, Wareham NJ, Zhao JH, Wilson JF, Joshi PK, Stubbe B, Rawal R, Schulz H, Imboden M, Probst-Hensch NM, Karrasch S, Gieger C, Deary IJ, Harris SE, Marten J, Rudan I, Enroth S, Gyllensten U, Kerr SM, Polasek O, Kähönen M, Surakka I, Vitart V, Hayward C, Lehtimäki T, Raitakari OT, Evans DM, Henderson AJ, Pennell CE, Wang CA, Sly PD, Wan ES, Busch R, Hobbs BD, Litonjua AA, Sparrow DW, Gulsvik A, Bakke PS, Crapo JD, Beaty TH, Hansel NN, Mathias RA, Ruczinski I, Barnes KC, Bossé Y, Joubert P, van den Berge M, Brandsma CA, Paré PD, Sin DD, Nickle DC, Hao K, Gottesman O, Dewey FE, Bruse SE, Carey DJ, Kirchner HL, Jonsson S, Thorleifsson G, Jonsdottir I, Gislason T, Stefansson K, Schurmann C, Nadkarni G, Bottinger EP, Loos RJ, Walters RG, Chen Z, Millwood IY, Vaucher J, Kurmi OP, Li L, Hansell AL, Brightling C, Zeggini E, Cho MH, Silverman EK, Sayers I, Trynka G, Morris AP, Strachan DP, Hall IP, and Tobin MD
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Asthma genetics, Epigenesis, Genetic genetics, Female, Genome-Wide Association Study methods, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Risk Factors, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Lung physiopathology, Pulmonary Disease, Chronic Obstructive genetics
- Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10
-49 ), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.- Published
- 2017
- Full Text
- View/download PDF
10. The impact of low-frequency and rare variants on lipid levels.
- Author
-
Surakka I, Horikoshi M, Mägi R, Sarin AP, Mahajan A, Lagou V, Marullo L, Ferreira T, Miraglio B, Timonen S, Kettunen J, Pirinen M, Karjalainen J, Thorleifsson G, Hägg S, Hottenga JJ, Isaacs A, Ladenvall C, Beekman M, Esko T, Ried JS, Nelson CP, Willenborg C, Gustafsson S, Westra HJ, Blades M, de Craen AJ, de Geus EJ, Deelen J, Grallert H, Hamsten A, Havulinna AS, Hengstenberg C, Houwing-Duistermaat JJ, Hyppönen E, Karssen LC, Lehtimäki T, Lyssenko V, Magnusson PK, Mihailov E, Müller-Nurasyid M, Mpindi JP, Pedersen NL, Penninx BW, Perola M, Pers TH, Peters A, Rung J, Smit JH, Steinthorsdottir V, Tobin MD, Tsernikova N, van Leeuwen EM, Viikari JS, Willems SM, Willemsen G, Schunkert H, Erdmann J, Samani NJ, Kaprio J, Lind L, Gieger C, Metspalu A, Slagboom PE, Groop L, van Duijn CM, Eriksson JG, Jula A, Salomaa V, Boomsma DI, Power C, Raitakari OT, Ingelsson E, Järvelin MR, Thorsteinsdottir U, Franke L, Ikonen E, Kallioniemi O, Pietiäinen V, Lindgren CM, Stefansson K, Palotie A, McCarthy MI, Morris AP, Prokopenko I, and Ripatti S
- Subjects
- Dyslipidemias genetics, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mutation, Missense, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Lipid Metabolism genetics
- Abstract
Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
- Published
- 2015
- Full Text
- View/download PDF
11. Genome-wide association analysis identifies six new loci associated with forced vital capacity.
- Author
-
Loth DW, Soler Artigas M, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C, Lee MK, Strachan DP, James AL, Huffman JE, Vitart V, Ramasamy A, Wareham NJ, Kaprio J, Wang XQ, Trochet H, Kähönen M, Flexeder C, Albrecht E, Lopez LM, de Jong K, Thyagarajan B, Alves AC, Enroth S, Omenaas E, Joshi PK, Fall T, Viñuela A, Launer LJ, Loehr LR, Fornage M, Li G, Wilk JB, Tang W, Manichaikul A, Lahousse L, Harris TB, North KE, Rudnicka AR, Hui J, Gu X, Lumley T, Wright AF, Hastie ND, Campbell S, Kumar R, Pin I, Scott RA, Pietiläinen KH, Surakka I, Liu Y, Holliday EG, Schulz H, Heinrich J, Davies G, Vonk JM, Wojczynski M, Pouta A, Johansson A, Wild SH, Ingelsson E, Rivadeneira F, Völzke H, Hysi PG, Eiriksdottir G, Morrison AC, Rotter JI, Gao W, Postma DS, White WB, Rich SS, Hofman A, Aspelund T, Couper D, Smith LJ, Psaty BM, Lohman K, Burchard EG, Uitterlinden AG, Garcia M, Joubert BR, McArdle WL, Musk AB, Hansel N, Heckbert SR, Zgaga L, van Meurs JB, Navarro P, Rudan I, Oh YM, Redline S, Jarvis DL, Zhao JH, Rantanen T, O'Connor GT, Ripatti S, Scott RJ, Karrasch S, Grallert H, Gaddis NC, Starr JM, Wijmenga C, Minster RL, Lederer DJ, Pekkanen J, Gyllensten U, Campbell H, Morris AP, Gläser S, Hammond CJ, Burkart KM, Beilby J, Kritchevsky SB, Gudnason V, Hancock DB, Williams OD, Polasek O, Zemunik T, Kolcic I, Petrini MF, Wjst M, Kim WJ, Porteous DJ, Scotland G, Smith BH, Viljanen A, Heliövaara M, Attia JR, Sayers I, Hampel R, Gieger C, Deary IJ, Boezen HM, Newman A, Jarvelin MR, Wilson JF, Lind L, Stricker BH, Teumer A, Spector TD, Melén E, Peters MJ, Lange LA, Barr RG, Bracke KR, Verhamme FM, Sung J, Hiemstra PS, Cassano PA, Sood A, Hayward C, Dupuis J, Hall IP, Brusselle GG, Tobin MD, and London SJ
- Subjects
- Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Predisposition to Disease, Humans, Lung Diseases pathology, Meta-Analysis as Topic, Polymorphism, Single Nucleotide genetics, Prognosis, Quantitative Trait Loci genetics, Respiratory Function Tests, Spirometry, Genetic Loci genetics, Genome, Human, Genome-Wide Association Study, Lung Diseases genetics, Vital Capacity genetics
- Abstract
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
- Published
- 2014
- Full Text
- View/download PDF
12. Discovery and refinement of loci associated with lipid levels.
- Author
-
Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Do R, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkilä K, Hyppönen E, Isaacs A, Jackson AU, Johansson Å, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J, Lyytikäinen LP, Magnusson PKE, Mangino M, Mihailov E, Montasser ME, Müller-Nurasyid M, Nolte IM, O'Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney ASF, Döring A, Elliott P, Epstein SE, Ingi Eyjolfsson G, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJP, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimäki T, Lin SY, Lindström J, Loos RJF, Mach F, McArdle WL, Meisinger C, Mitchell BD, Müller G, Nagaraja R, Narisu N, Nieminen TVM, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stančáková A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YI, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrières J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Järvelin MR, Jula A, Kähönen M, Kaprio J, Kesäniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, März W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njølstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PEH, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BHR, Ordovas JM, Boerwinkle E, Palmer CNA, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Kathiresan S, Mohlke KL, Ingelsson E, and Abecasis GR
- Subjects
- Asian People genetics, Black People genetics, Cholesterol, HDL blood, Cholesterol, HDL genetics, Cholesterol, LDL blood, Cholesterol, LDL genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Triglycerides blood, Triglycerides genetics, White People genetics, Coronary Artery Disease blood, Coronary Artery Disease genetics, Lipids blood, Lipids genetics
- Abstract
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
- Published
- 2013
- Full Text
- View/download PDF
13. Common variants associated with plasma triglycerides and risk for coronary artery disease.
- Author
-
Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkilä K, Hyppönen E, Isaacs A, Jackson AU, Johansson A, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J, Lyytikäinen LP, Magnusson PK, Mangino M, Mihailov E, Montasser ME, Müller-Nurasyid M, Nolte IM, O'Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney AS, Döring A, Elliott P, Epstein SE, Eyjolfsson GI, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJ, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimäki T, Lin SY, Lindström J, Loos RJ, Mach F, McArdle WL, Meisinger C, Mitchell BD, Müller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stančáková A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YD, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrières J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Järvelin MR, Jula A, Kähönen M, Kaprio J, Kesäniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, März W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njølstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PE, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BH, Altshuler D, Ordovas JM, Boerwinkle E, Palmer CN, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Mohlke KL, Ingelsson E, Abecasis GR, Daly MJ, Neale BM, and Kathiresan S
- Subjects
- Biological Transport, Cholesterol, HDL blood, Cholesterol, LDL blood, Coronary Artery Disease epidemiology, Coronary Artery Disease genetics, Humans, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides metabolism, Cholesterol, HDL genetics, Cholesterol, LDL genetics, Coronary Artery Disease blood, Triglycerides blood, Triglycerides genetics
- Abstract
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
- Published
- 2013
- Full Text
- View/download PDF
14. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
- Author
-
Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau-Chonka DC, Day FR, Esko T, Fall T, Ferreira T, Gentilini D, Jackson AU, Luan J, Randall JC, Vedantam S, Willer CJ, Winkler TW, Wood AR, Workalemahu T, Hu YJ, Lee SH, Liang L, Lin DY, Min JL, Neale BM, Thorleifsson G, Yang J, Albrecht E, Amin N, Bragg-Gresham JL, Cadby G, den Heijer M, Eklund N, Fischer K, Goel A, Hottenga JJ, Huffman JE, Jarick I, Johansson Å, Johnson T, Kanoni S, Kleber ME, König IR, Kristiansson K, Kutalik Z, Lamina C, Lecoeur C, Li G, Mangino M, McArdle WL, Medina-Gomez C, Müller-Nurasyid M, Ngwa JS, Nolte IM, Paternoster L, Pechlivanis S, Perola M, Peters MJ, Preuss M, Rose LM, Shi J, Shungin D, Smith AV, Strawbridge RJ, Surakka I, Teumer A, Trip MD, Tyrer J, Van Vliet-Ostaptchouk JV, Vandenput L, Waite LL, Zhao JH, Absher D, Asselbergs FW, Atalay M, Attwood AP, Balmforth AJ, Basart H, Beilby J, Bonnycastle LL, Brambilla P, Bruinenberg M, Campbell H, Chasman DI, Chines PS, Collins FS, Connell JM, Cookson WO, de Faire U, de Vegt F, Dei M, Dimitriou M, Edkins S, Estrada K, Evans DM, Farrall M, Ferrario MM, Ferrières J, Franke L, Frau F, Gejman PV, Grallert H, Grönberg H, Gudnason V, Hall AS, Hall P, Hartikainen AL, Hayward C, Heard-Costa NL, Heath AC, Hebebrand J, Homuth G, Hu FB, Hunt SE, Hyppönen E, Iribarren C, Jacobs KB, Jansson JO, Jula A, Kähönen M, Kathiresan S, Kee F, Khaw KT, Kivimäki M, Koenig W, Kraja AT, Kumari M, Kuulasmaa K, Kuusisto J, Laitinen JH, Lakka TA, Langenberg C, Launer LJ, Lind L, Lindström J, Liu J, Liuzzi A, Lokki ML, Lorentzon M, Madden PA, Magnusson PK, Manunta P, Marek D, März W, Mateo Leach I, McKnight B, Medland SE, Mihailov E, Milani L, Montgomery GW, Mooser V, Mühleisen TW, Munroe PB, Musk AW, Narisu N, Navis G, Nicholson G, Nohr EA, Ong KK, Oostra BA, Palmer CN, Palotie A, Peden JF, Pedersen N, Peters A, Polasek O, Pouta A, Pramstaller PP, Prokopenko I, Pütter C, Radhakrishnan A, Raitakari O, Rendon A, Rivadeneira F, Rudan I, Saaristo TE, Sambrook JG, Sanders AR, Sanna S, Saramies J, Schipf S, Schreiber S, Schunkert H, Shin SY, Signorini S, Sinisalo J, Skrobek B, Soranzo N, Stančáková A, Stark K, Stephens JC, Stirrups K, Stolk RP, Stumvoll M, Swift AJ, Theodoraki EV, Thorand B, Tregouet DA, Tremoli E, Van der Klauw MM, van Meurs JB, Vermeulen SH, Viikari J, Virtamo J, Vitart V, Waeber G, Wang Z, Widén E, Wild SH, Willemsen G, Winkelmann BR, Witteman JC, Wolffenbuttel BH, Wong A, Wright AF, Zillikens MC, Amouyel P, Boehm BO, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Cupples LA, Cusi D, Dedoussis GV, Erdmann J, Eriksson JG, Franks PW, Froguel P, Gieger C, Gyllensten U, Hamsten A, Harris TB, Hengstenberg C, Hicks AA, Hingorani A, Hinney A, Hofman A, Hovingh KG, Hveem K, Illig T, Jarvelin MR, Jöckel KH, Keinanen-Kiukaanniemi SM, Kiemeney LA, Kuh D, Laakso M, Lehtimäki T, Levinson DF, Martin NG, Metspalu A, Morris AD, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Ouwehand WH, Palmer LJ, Penninx B, Power C, Province MA, Psaty BM, Qi L, Rauramaa R, Ridker PM, Ripatti S, Salomaa V, Samani NJ, Snieder H, Sørensen TI, Spector TD, Stefansson K, Tönjes A, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Vollenweider P, Wallaschofski H, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Abecasis GR, Assimes TL, Barroso I, Boehnke M, Borecki IB, Deloukas P, Fox CS, Frayling T, Groop LC, Haritunian T, Heid IM, Hunter D, Kaplan RC, Karpe F, Moffatt MF, Mohlke KL, O'Connell JR, Pawitan Y, Schadt EE, Schlessinger D, Steinthorsdottir V, Strachan DP, Thorsteinsdottir U, van Duijn CM, Visscher PM, Di Blasio AM, Hirschhorn JN, Lindgren CM, Morris AP, Meyre D, Scherag A, McCarthy MI, Speliotes EK, North KE, Loos RJ, and Ingelsson E
- Subjects
- Body Mass Index, Case-Control Studies, Genotype, Humans, Meta-Analysis as Topic, Phenotype, Waist-Hip Ratio, White People genetics, Anthropometry, Body Height genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Obesity genetics, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci
- Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
- Published
- 2013
- Full Text
- View/download PDF
15. 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, Hägg S, Matthews MK, Palmen J, Norata GD, O'Reilly PF, Saleheen D, Amin N, Balmforth AJ, Beekman M, de Boer RA, Böhringer S, Braund PS, Burton PR, de Craen AJ, Denniff M, Dong Y, Douroudis K, Dubinina E, Eriksson JG, Garlaschelli K, Guo D, Hartikainen AL, Henders AK, Houwing-Duistermaat JJ, Kananen L, Karssen LC, Kettunen J, Klopp N, Lagou V, van Leeuwen EM, Madden PA, Mägi R, Magnusson PK, Männistö S, McCarthy MI, Medland SE, Mihailov E, Montgomery GW, Oostra BA, Palotie A, Peters A, Pollard H, Pouta A, Prokopenko I, Ripatti S, Salomaa V, Suchiman HE, Valdes AM, Verweij N, Viñuela A, Wang X, Wichmann HE, Widen E, Willemsen G, Wright MJ, Xia K, Xiao X, van Veldhuisen DJ, Catapano AL, Tobin MD, Hall AS, Blakemore AI, van Gilst WH, Zhu H, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Talmud PJ, Pedersen NL, 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
- Subjects
- Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Risk Factors, Biomarkers, Tumor genetics, Disease genetics, Genetic Loci genetics, Leukocytes metabolism, Telomerase genetics, Telomere genetics
- 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
- Full Text
- View/download PDF
16. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- Author
-
Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, Zhai G, Zhao JH, Smith AV, Huffman JE, Albrecht E, Jackson CM, Evans DM, Cadby G, Fornage M, Manichaikul A, Lopez LM, Johnson T, Aldrich MC, Aspelund T, Barroso I, Campbell H, Cassano PA, Couper DJ, Eiriksdottir G, Franceschini N, Garcia M, Gieger C, Gislason GK, Grkovic I, Hammond CJ, Hancock DB, Harris TB, Ramasamy A, Heckbert SR, Heliövaara M, Homuth G, Hysi PG, James AL, Jankovic S, Joubert BR, Karrasch S, Klopp N, Koch B, Kritchevsky SB, Launer LJ, Liu Y, Loehr LR, Lohman K, Loos RJ, Lumley T, Al Balushi KA, Ang WQ, Barr RG, Beilby J, Blakey JD, Boban M, Boraska V, Brisman J, Britton JR, Brusselle GG, Cooper C, Curjuric I, Dahgam S, Deary IJ, Ebrahim S, Eijgelsheim M, Francks C, Gaysina D, Granell R, Gu X, Hankinson JL, Hardy R, Harris SE, Henderson J, Henry A, Hingorani AD, Hofman A, Holt PG, Hui J, Hunter ML, Imboden M, Jameson KA, Kerr SM, Kolcic I, Kronenberg F, Liu JZ, Marchini J, McKeever T, Morris AD, Olin AC, Porteous DJ, Postma DS, Rich SS, Ring SM, Rivadeneira F, Rochat T, Sayer AA, Sayers I, Sly PD, Smith GD, Sood A, Starr JM, Uitterlinden AG, Vonk JM, Wannamethee SG, Whincup PH, Wijmenga C, Williams OD, Wong A, Mangino M, Marciante KD, McArdle WL, Meibohm B, Morrison AC, North KE, Omenaas E, Palmer LJ, Pietiläinen KH, Pin I, Pola Sbreve Ek O, Pouta A, Psaty BM, Hartikainen AL, Rantanen T, Ripatti S, Rotter JI, Rudan I, Rudnicka AR, Schulz H, Shin SY, Spector TD, Surakka I, Vitart V, Völzke H, Wareham NJ, Warrington NM, Wichmann HE, Wild SH, Wilk JB, Wjst M, Wright AF, Zgaga L, Zemunik T, Pennell CE, Nyberg F, Kuh D, Holloway JW, Boezen HM, Lawlor DA, Morris RW, Probst-Hensch N, Kaprio J, Wilson JF, Hayward C, Kähönen M, Heinrich J, Musk AW, Jarvis DL, Gläser S, Järvelin MR, Ch Stricker BH, Elliott P, O'Connor GT, Strachan DP, London SJ, Hall IP, Gudnason V, and Tobin MD
- Subjects
- Child, Humans, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive physiopathology, White People, Genome-Wide Association Study, Respiratory Function Tests
- Abstract
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
- Published
- 2011
- Full Text
- View/download PDF
17. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
- Author
-
Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, Thorleifsson G, Zillikens MC, Speliotes EK, Mägi R, Workalemahu T, White CC, Bouatia-Naji N, Harris TB, Berndt SI, Ingelsson E, Willer CJ, Weedon MN, Luan J, Vedantam S, Esko T, Kilpeläinen TO, Kutalik Z, Li S, Monda KL, Dixon AL, Holmes CC, Kaplan LM, Liang L, Min JL, Moffatt MF, Molony C, Nicholson G, Schadt EE, Zondervan KT, Feitosa MF, Ferreira T, Lango Allen H, Weyant RJ, Wheeler E, Wood AR, Estrada K, Goddard ME, Lettre G, Mangino M, Nyholt DR, Purcell S, Smith AV, Visscher PM, Yang J, McCarroll SA, Nemesh J, Voight BF, Absher D, Amin N, Aspelund T, Coin L, Glazer NL, Hayward C, Heard-Costa NL, Hottenga JJ, Johansson A, Johnson T, Kaakinen M, Kapur K, Ketkar S, Knowles JW, Kraft P, Kraja AT, Lamina C, Leitzmann MF, McKnight B, Morris AP, Ong KK, Perry JR, Peters MJ, Polasek O, Prokopenko I, Rayner NW, Ripatti S, Rivadeneira F, Robertson NR, Sanna S, Sovio U, Surakka I, Teumer A, van Wingerden S, Vitart V, Zhao JH, Cavalcanti-Proença C, Chines PS, Fisher E, Kulzer JR, Lecoeur C, Narisu N, Sandholt C, Scott LJ, Silander K, Stark K, Tammesoo ML, Teslovich TM, Timpson NJ, Watanabe RM, Welch R, Chasman DI, Cooper MN, Jansson JO, Kettunen J, Lawrence RW, Pellikka N, Perola M, Vandenput L, Alavere H, Almgren P, Atwood LD, Bennett AJ, Biffar R, Bonnycastle LL, Bornstein SR, Buchanan TA, Campbell H, Day IN, Dei M, Dörr M, Elliott P, Erdos MR, Eriksson JG, Freimer NB, Fu M, Gaget S, Geus EJ, Gjesing AP, Grallert H, Grässler J, Groves CJ, Guiducci C, Hartikainen AL, Hassanali N, Havulinna AS, Herzig KH, Hicks AA, Hui J, Igl W, Jousilahti P, Jula A, Kajantie E, Kinnunen L, Kolcic I, Koskinen S, Kovacs P, Kroemer HK, Krzelj V, Kuusisto J, Kvaloy K, Laitinen J, Lantieri O, Lathrop GM, Lokki ML, Luben RN, Ludwig B, McArdle WL, McCarthy A, Morken MA, Nelis M, Neville MJ, Paré G, Parker AN, Peden JF, Pichler I, Pietiläinen KH, Platou CG, Pouta A, Ridderstråle M, Samani NJ, Saramies J, Sinisalo J, Smit JH, Strawbridge RJ, Stringham HM, Swift AJ, Teder-Laving M, Thomson B, Usala G, van Meurs JB, van Ommen GJ, Vatin V, Volpato CB, Wallaschofski H, Walters GB, Widen E, Wild SH, Willemsen G, Witte DR, Zgaga L, Zitting P, Beilby JP, James AL, Kähönen M, Lehtimäki T, Nieminen MS, Ohlsson C, Palmer LJ, Raitakari O, Ridker PM, Stumvoll M, Tönjes A, Viikari J, Balkau B, Ben-Shlomo Y, Bergman RN, Boeing H, Smith GD, Ebrahim S, Froguel P, Hansen T, Hengstenberg C, Hveem K, Isomaa B, Jørgensen T, Karpe F, Khaw KT, Laakso M, Lawlor DA, Marre M, Meitinger T, Metspalu A, Midthjell K, Pedersen O, Salomaa V, Schwarz PE, Tuomi T, Tuomilehto J, Valle TT, Wareham NJ, Arnold AM, Beckmann JS, Bergmann S, Boerwinkle E, Boomsma DI, Caulfield MJ, Collins FS, Eiriksdottir G, Gudnason V, Gyllensten U, Hamsten A, Hattersley AT, Hofman A, Hu FB, Illig T, Iribarren C, Jarvelin MR, Kao WH, Kaprio J, Launer LJ, Munroe PB, Oostra B, Penninx BW, Pramstaller PP, Psaty BM, Quertermous T, Rissanen A, Rudan I, Shuldiner AR, Soranzo N, Spector TD, Syvanen AC, Uda M, Uitterlinden A, Völzke H, Vollenweider P, Wilson JF, Witteman JC, Wright AF, Abecasis GR, Boehnke M, Borecki IB, Deloukas P, Frayling TM, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, North KE, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, Hirschhorn JN, Assimes TL, Wichmann HE, Thorsteinsdottir U, van Duijn CM, Stefansson K, Cupples LA, Loos RJ, Barroso I, McCarthy MI, Fox CS, Mohlke KL, and Lindgren CM
- Subjects
- Adipose Tissue anatomy & histology, Age Factors, Chromosome Mapping, Female, Genome, Human, Humans, Male, Meta-Analysis as Topic, Sex Characteristics, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Waist-Hip Ratio
- Abstract
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
- Published
- 2010
- Full Text
- View/download PDF
18. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
- Author
-
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Lango Allen H, Lindgren CM, Luan J, Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpeläinen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proença C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, den Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grässler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jørgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, König IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaløy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimäki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, 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, Robertson NR, 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, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tönjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, 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, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Grönberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, McCarroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, McCarthy MI, Hirschhorn JN, Ingelsson E, and Loos RJ
- Subjects
- Body Size genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Humans, Obesity genetics, Polymorphism, Single Nucleotide, White People genetics, Body Height genetics, Body Mass Index, Body Weight genetics, Chromosome Mapping
- Abstract
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
- Published
- 2010
- Full Text
- View/download PDF
19. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.
- Author
-
Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Sulem P, Rafnar T, Esko T, Walter S, Gieger C, Rawal R, Mangino M, Prokopenko I, Mägi R, Keskitalo K, Gudjonsdottir IH, Gretarsdottir S, Stefansson H, Thompson JR, Aulchenko YS, Nelis M, Aben KK, den Heijer M, Dirksen A, Ashraf H, Soranzo N, Valdes AM, Steves C, Uitterlinden AG, Hofman A, Tönjes A, Kovacs P, Hottenga JJ, Willemsen G, Vogelzangs N, Döring A, Dahmen N, Nitz B, Pergadia ML, Saez B, De Diego V, Lezcano V, Garcia-Prats MD, Ripatti S, Perola M, Kettunen J, Hartikainen AL, Pouta A, Laitinen J, Isohanni M, Huei-Yi S, Allen M, Krestyaninova M, Hall AS, Jones GT, van Rij AM, Mueller T, Dieplinger B, Haltmayer M, Jonsson S, Matthiasson SE, Oskarsson H, Tyrfingsson T, Kiemeney LA, Mayordomo JI, Lindholt JS, Pedersen JH, Franklin WA, Wolf H, Montgomery GW, Heath AC, Martin NG, Madden PA, Giegling I, Rujescu D, Järvelin MR, Salomaa V, Stumvoll M, Spector TD, Wichmann HE, Metspalu A, Samani NJ, Penninx BW, Oostra BA, Boomsma DI, Tiemeier H, van Duijn CM, Kaprio J, Gulcher JR, McCarthy MI, Peltonen L, Thorsteinsdottir U, and Stefansson K
- Subjects
- Alleles, Cohort Studies, Cytochrome P-450 CYP2A6, Female, Genome-Wide Association Study, Genomics, Humans, Lung Neoplasms genetics, Male, Odds Ratio, Phenotype, Tobacco Use Disorder genetics, Aryl Hydrocarbon Hydroxylases genetics, Genetic Variation, Receptors, Nicotinic genetics, Smoking genetics
- Abstract
Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
- Published
- 2010
- Full Text
- View/download PDF
20. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
- Author
-
Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, Lange LA, Bradfield JP, Kerkhof M, Marsh JA, Mägi R, Chen CM, Lyon HN, Kirin M, Adair LS, Aulchenko YS, Bennett AJ, Borja JB, Bouatia-Naji N, Charoen P, Coin LJ, Cousminer DL, de Geus EJ, Deloukas P, Elliott P, Evans DM, Froguel P, Glaser B, Groves CJ, Hartikainen AL, Hassanali N, Hirschhorn JN, Hofman A, Holly JM, Hyppönen E, Kanoni S, Knight BA, Laitinen J, Lindgren CM, McArdle WL, O'Reilly PF, Pennell CE, Postma DS, Pouta A, Ramasamy A, Rayner NW, Ring SM, Rivadeneira F, Shields BM, Strachan DP, Surakka I, Taanila A, Tiesler C, Uitterlinden AG, van Duijn CM, Wijga AH, Willemsen G, Zhang H, Zhao J, Wilson JF, Steegers EA, Hattersley AT, Eriksson JG, Peltonen L, Mohlke KL, Grant SF, Hakonarson H, Koppelman GH, Dedoussis GV, Heinrich J, Gillman MW, Palmer LJ, Frayling TM, Boomsma DI, Davey Smith G, Power C, Jaddoe VW, Jarvelin MR, and McCarthy MI
- Subjects
- Alleles, Birth Weight, Cohort Studies, Diabetes Mellitus, Type 2 genetics, Ethnicity, Female, Genetic Predisposition to Disease, Genotype, Glucose metabolism, Humans, Male, Models, Genetic, Pregnancy, Adenylyl Cyclases genetics, Cyclins genetics, Isoenzymes genetics
- Abstract
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
- Published
- 2010
- Full Text
- View/download PDF
21. Genome-wide association study identifies five loci associated with lung function.
- Author
-
Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Henderson J, Granell R, McArdle WL, Rudnicka AR, Barroso I, Loos RJ, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, Hartikainen AL, Peltonen L, Gyllensten U, Johansson A, Zaboli G, Campbell H, Wild SH, Wilson JF, Gläser S, Homuth G, Völzke H, Mangino M, Soranzo N, Spector TD, Polasek O, Rudan I, Wright AF, Heliövaara M, Ripatti S, Pouta A, Naluai AT, Olin AC, Torén K, Cooper MN, James AL, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Smith GD, Ebrahim S, McKeever TM, Pavord ID, MacLeod AK, Morris AD, Porteous DJ, Cooper C, Dennison E, Shaheen S, Karrasch S, Schnabel E, Schulz H, Grallert H, Bouatia-Naji N, Delplanque J, Froguel P, Blakey JD, Britton JR, Morris RW, Holloway JW, Lawlor DA, Hui J, Nyberg F, Jarvelin MR, Jackson C, Kähönen M, Kaprio J, Probst-Hensch NM, Koch B, Hayward C, Evans DM, Elliott P, Strachan DP, Hall IP, and Tobin MD
- Subjects
- Female, Forced Expiratory Volume, Glutathione Transferase genetics, Humans, Lung metabolism, Lung physiopathology, Male, Meta-Analysis as Topic, Microfilament Proteins genetics, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive physiopathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor for Advanced Glycation End Products, Receptors, Immunologic genetics, Receptors, Serotonin, 5-HT4 genetics, Respiratory Function Tests, Spirometry, Tensins, Thrombospondins genetics, Vital Capacity, Gene Expression Profiling, Genome, Human genetics, Genome-Wide Association Study methods, Lung physiology
- Abstract
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
- Published
- 2010
- Full Text
- View/download PDF
22. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.
- Author
-
Soranzo N, Spector TD, Mangino M, Kühnel B, Rendon A, Teumer A, Willenborg C, Wright B, Chen L, Li M, Salo P, Voight BF, Burns P, Laskowski RA, Xue Y, Menzel S, Altshuler D, Bradley JR, Bumpstead S, Burnett MS, Devaney J, Döring A, Elosua R, Epstein SE, Erber W, Falchi M, Garner SF, Ghori MJ, Goodall AH, Gwilliam R, Hakonarson HH, Hall AS, Hammond N, Hengstenberg C, Illig T, König IR, Knouff CW, McPherson R, Melander O, Mooser V, Nauck M, Nieminen MS, O'Donnell CJ, Peltonen L, Potter SC, Prokisch H, Rader DJ, Rice CM, Roberts R, Salomaa V, Sambrook J, Schreiber S, Schunkert H, Schwartz SM, Serbanovic-Canic J, Sinisalo J, Siscovick DS, Stark K, Surakka I, Stephens J, Thompson JR, Völker U, Völzke H, Watkins NA, Wells GA, Wichmann HE, Van Heel DA, Tyler-Smith C, Thein SL, Kathiresan S, Perola M, Reilly MP, Stewart AF, Erdmann J, Samani NJ, Meisinger C, Greinacher A, Deloukas P, Ouwehand WH, and Gieger C
- Subjects
- Blood Cell Count, Chromosomes, Human, Pair 12, Coronary Artery Disease genetics, Genetic Markers, Humans, Polymorphism, Single Nucleotide, Selection, Genetic, Blood Cells cytology, Genome, Human, Genome-Wide Association Study
- Abstract
The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Books, media, physical & digital resources
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.