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Veryan Codd,
Christopher P Nelson,
Eva Albrecht,
Massimo Mangino,
Joris Deelen,
Jessica L Buxton,
Jouke Jan Hottenga,
Krista Fischer,
Tõnu Esko,
Ida Surakka, [......],
Iiris Hovatta,
Christian Gieger,
Andres Metspalu,
Dorret I Boomsma,
Marjo-Riitta Jarvelin,
P Eline Slagboom,
John R Thompson,
Tim D Spector,
Pim van der Harst,
Nilesh J Samani
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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.
Nature Genetics 03/2013; 45(4):422-427. · 35.53 Impact Factor
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Ayşe Demirkan,
Cornelia M van Duijn,
Peter Ugocsai,
Aaron Isaacs,
Peter P Pramstaller,
Gerhard Liebisch,
James F Wilson,
Åsa Johansson,
Igor Rudan,
Yurii S Aulchenko, [......],
Jacqueline C M Witteman,
Tatiana Axenovich,
Ben A Oostra,
Thomas Meitinger,
Andrew A Hicks,
Caroline Hayward,
Alan F Wright,
Ulf Gyllensten,
Harry Campbell,
Gerd Schmitz
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ABSTRACT: Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.
PLoS Genetics 02/2012; 8(2):e1002490. · 8.69 Impact Factor
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Ida Surakka,
Aaron Isaacs, Lennart C Karssen,
Pirkka-Pekka P Laurila,
Rita P S Middelberg,
Emmi Tikkanen,
Janina S Ried,
Claudia Lamina,
Massimo Mangino,
Wilmar Igl, [......],
H-Erich Wichmann,
Christian Gieger,
Marjo-Riitta Järvelin,
Nicholas G Martin,
Albert Hofman,
Mark I McCarthy,
Leena Peltonen,
Cornelia M van Duijn,
Yurii S Aulchenko,
Samuli Ripatti
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ABSTRACT: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
PLoS Genetics 10/2011; 7(10):e1002333. · 8.69 Impact Factor
