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Sonja I Berndt,
Stefan Gustafsson,
Reedik Mägi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
André Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
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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.
Nature Genetics 04/2013; · 35.53 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Magi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
Andre Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
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.
Nature Genetics 04/2013; · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression based on approximately 400K SNPs and 50K transcripts in 400 sib pairs from the MRCA family panel has been widely used to interpret the results of GWAS. Here, we more than double the size of our initial dataset with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole genome expression array. We have used new statistical methods for dimension reduction to account for non-genetic effects in estimates of expression levels and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false discovery rates and increased the number of eQTLs mapped either locally or at a distance (i.e. in cis or trans) from 1,534 in the MRCA dataset to 4,452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7,302. Using the same methods and imputed SNPs in the newly acquired MRCE dataset we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes.
Genome Research 01/2013; · 13.61 Impact Factor
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Najaf Amin,
Jouke-Jan Hottenga,
Narelle K Hansell,
A Cecile Jw Janssens,
Marleen Hm de Moor,
Pamela Af Madden,
Irina V Zorkoltseva,
Brenda W Penninx,
Antonio Terracciano,
Manuela Uda, [......],
Michele L Pergadia,
Sarah E Medland,
Tatiana I Axenovich,
Eco de Geus,
Grant W Montgomery,
Margaret J Wright,
Ben A Oostra,
Nicholas G Martin,
Dorret I Boomsma,
Cornelia M van Duijn
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[hide abstract]
ABSTRACT: Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.European Journal of Human Genetics advance online publication, 5 December 2012; doi:10.1038/ejhg.2012.263.
European journal of human genetics: EJHG 12/2012; · 3.56 Impact Factor
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Jian Yang,
Ruth J F Loos,
Joseph E Powell,
Sarah E Medland,
Elizabeth K Speliotes,
Daniel I Chasman,
Lynda M Rose,
Gudmar Thorleifsson,
Valgerdur Steinthorsdottir,
Reedik Mägi, [......],
David P Strachan,
William G Hill,
Harold Snieder,
Paul M Ridker,
Unnur Thorsteinsdottir,
Kari Stefansson,
Timothy M Frayling,
Joel N Hirschhorn,
Michael E Goddard,
Peter M Visscher
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ABSTRACT: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
Nature 09/2012; 490(7419):267-72. · 36.28 Impact Factor
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Andrew P Morris,
Benjamin F Voight,
Tanya M Teslovich,
Teresa Ferreira,
Ayellet V Segrè,
Valgerdur Steinthorsdottir,
Rona J Strawbridge,
Hassan Khan,
Harald Grallert,
Anubha Mahajan, [......],
Unnur Thorsteinsdottir,
Leif C Groop,
Kari Stefansson,
Frank Hu,
James S Pankow,
Josée Dupuis,
James B Meigs,
David Altshuler,
Michael Boehnke,
Mark I McCarthy
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Andrew P Morris,
Benjamin F Voight,
Tanya M Teslovich,
Teresa Ferreira,
Ayellet V Segrè,
Valgerdur Steinthorsdottir,
Rona J Strawbridge,
Hassan Khan,
Harald Grallert,
Anubha Mahajan, [......],
Unnur Thorsteinsdottir,
Leif C Groop,
Kari Stefansson,
Frank Hu,
James S Pankow,
Josée Dupuis,
James B Meigs,
David Altshuler,
Michael Boehnke,
Mark I McCarthy
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ABSTRACT: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
Nature Genetics 08/2012; 44(9):981-90. · 35.53 Impact Factor
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Zari Dastani,
Marie-France Hivert,
Nicholas Timpson,
John R B Perry,
Xin Yuan,
Robert A Scott,
Peter Henneman,
Iris M Heid,
Jorge R Kizer,
Leo-Pekka Lyytikäinen, [......],
Eric E Schadt,
David P Strachan,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Sekar Kathiresan
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ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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Nicholette D Palmer,
Caitrin W McDonough,
Pamela J Hicks,
Bong H Roh,
Maria R Wing,
S Sandy An,
Jessica M Hester,
Jessica N Cooke,
Meredith A Bostrom,
Megan E Rudock, [......],
Angelo Scuteri,
David Schlessinger,
Manuela Uda,
Aimo Ruokonen,
Marjo-Riitta Jarvelin,
Dawn M Waterworth,
Peter Vollenweider,
Leena Peltonen,
Vincent Mooser,
Robert Sladek
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ABSTRACT: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
PLoS ONE 01/2012; 7(1):e29202. · 4.09 Impact Factor
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John C Chambers,
Weihua Zhang,
Joban Sehmi,
Xinzhong Li,
Mark N Wass,
Pim Van der Harst,
Hilma Holm,
Serena Sanna,
Maryam Kavousi,
Sebastian E Baumeister, [......],
Caroline S Fox,
Mika Ala-Korpela,
Kari Stefansson,
Peter Vollenweider,
Henry Völzke,
Eric E Schadt,
James Scott,
Marjo-Riitta Järvelin,
Paul Elliott,
Jaspal S Kooner
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ABSTRACT: Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.
Nature Genetics 11/2011; 43(11):1131-8. · 35.53 Impact Factor
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Louise V Wain,
Germaine C Verwoert,
Paul F O'Reilly,
Gang Shi,
Toby Johnson,
Andrew D Johnson,
Murielle Bochud,
Kenneth M Rice,
Peter Henneman,
Albert V Smith, [......],
Vilmundur Gudnason,
Christopher Newton-Cheh,
Daniel Levy,
Patricia B Munroe,
Bruce M Psaty,
Mark J Caulfield,
Dabeeru C Rao,
Martin D Tobin,
Paul Elliott,
Cornelia M van Duijn
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ABSTRACT: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Nature Genetics 09/2011; 43(10):1005-11. · 35.53 Impact Factor
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Gareth J McKay,
Chris C Patterson,
Usha Chakravarthy,
Shilpa Dasari,
Caroline C Klaver,
Johannes R Vingerling,
Lintje Ho,
Paulus T V M de Jong,
Astrid E Fletcher,
Ian S Young, [......],
Atsuhiro Kanda,
Wei Chen, Goncalo R Abecasis,
Alan F Wright,
Caroline Hayward,
Paul N Baird,
Robyn H Guymer,
John Attia,
Ammarin Thakkinstian,
Giuliana Silvestri
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ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
Human Mutation 08/2011; 32(12):1407-16. · 5.69 Impact Factor
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Jaspal S Kooner,
Danish Saleheen,
Xueling Sim,
Joban Sehmi,
Weihua Zhang,
Philippe Frossard,
Latonya F Been,
Kee-Seng Chia,
Antigone S Dimas,
Neelam Hassanali, [......],
Dharambir K Sanghera,
James Scott,
Mark Seielstad,
Paul Z Zimmet,
Paul Elliott,
Yik Ying Teo,
Mark I McCarthy,
John Danesh,
E Shyong Tai,
John C Chambers
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[hide abstract]
ABSTRACT: We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
Nature Genetics 08/2011; 43(10):984-9. · 35.53 Impact Factor
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Gareth J McKay,
Giuliana Silvestri,
Usha Chakravarthy,
Shilpa Dasari,
Lars G Fritsche,
Bernhard H Weber,
Claudia N Keilhauer,
Michael L Klein,
Peter J Francis,
Caroline C Klaver, [......],
Anthony T Moore,
Johan H Seland,
Mati Rahu,
Gisele Soubrane,
Laura Tomazzoli,
Fotis Topouzis,
Jesus Vioque,
Ian S Young,
Astrid E Fletcher,
Chris C Patterson
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ABSTRACT: Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
American journal of epidemiology 06/2011; 173(12):1357-64. · 5.59 Impact Factor
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ABSTRACT: Accurate genetic maps are required for successful and efficient linkage mapping of disease genes. However, most available genome-wide genetic maps were built using only small collections of pedigrees, and therefore have large sampling errors. A large set of genetic studies genotyped by the NHLBI Mammalian Genotyping Service (MGS) provide appropriate data for generating more accurate maps.
We collected a large sample of uncleaned genotype data for 461 markers generated by the MGS using the Weber screening sets 9 and 10. This collection includes genotypes for over 4,400 pedigrees containing over 17,000 genotyped individuals from different populations. We identified and cleaned numerous relationship and genotyping errors, as well as verified the marker orders. We used this dataset to test for population-specific genetic maps, and to re-estimate the genetic map distances with greater precision; standard errors for all intervals are provided. The map-interval sizes from the European (or European descent), Chinese, and Hispanic samples are in quite good agreement with each other. We found one map interval on chromosome 8p with a statistically significant size difference between the European and Chinese samples, and several map intervals with significant size differences between the African American and Chinese samples. When comparing Palauan with European samples, a statistically significant difference was detected at the telomeric region of chromosome 11p. Several significant differences were also identified between populations in chromosomal and genome lengths.
Our new population-specific screening set maps can be used to improve the accuracy of disease-mapping studies. As a result of the large sample size, the average length of the 95% confidence interval (CI) for a 10 cM map interval is only 2.4 cM, which is considerably smaller than on previously published maps.
BMC Medical Genetics 01/2011; 12:15. · 2.33 Impact Factor
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Theru A Sivakumaran,
Robert P Igo,
Jeffrey M Kidd,
Andy Itsara,
Laura J Kopplin,
Wei Chen,
Stephanie A Hagstrom,
Neal S Peachey,
Peter J Francis,
Michael L Klein, [......],
Lingam Vijaya,
Govindasamy Kumaramanickavel,
Tien Y Wong,
Anand Swaroop, Goncalo R Abecasis,
Ronald Klein,
Barbara E K Klein,
Deborah A Nickerson,
Evan E Eichler,
Sudha K Iyengar
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ABSTRACT: Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.
PLoS ONE 01/2011; 6(10):e25598. · 4.09 Impact Factor
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John C Chambers,
Weihua Zhang,
Graham M Lord,
Pim van der Harst,
Debbie A Lawlor,
Joban S Sehmi,
Daniel P Gale,
Mark N Wass,
Kourosh R Ahmadi,
Stephan J L Bakker, [......],
Patrick H Maxwell,
Mark I McCarthy,
Marjo-Riitta Jarvelin,
Vincent Mooser, Goncalo R Abecasis,
Liz Lightstone,
James Scott,
Gerjan Navis,
Paul Elliott,
Jaspal S Kooner
[show abstract]
[hide abstract]
ABSTRACT: Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
Nature Genetics 04/2010; 42(5):373-5. · 35.53 Impact Factor
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ABSTRACT: To further elucidate molecular alterations in psoriasis, we performed a gene expression study of 58 paired lesional and uninvolved psoriatic and 64 control skin samples. Comparison of involved psoriatic (PP) and normal (NN) skin identified 1,326 differentially regulated transcripts encoding 918 unique genes (549 up- and 369 downregulated), of which over 600 are to our knowledge previously unreported, including S100A7A, THRSP, and ELOVL3. Strongly upregulated genes included SERPINB4, PI3, DEFB4, and several S100-family members. Strongly downregulated genes included Wnt-inhibitory factor-1 (WIF1), beta-cellulin (BTC), and CCL27. Enriched gene ontology categories included immune response, defense response, and keratinocyte differentiation. Biological processes regulating fatty acid and lipid metabolism were enriched in the down-regulated gene set. Comparison of the psoriatic transcriptome to the transcriptomes of cytokine-stimulated cultured keratinocytes (IL-17, IL-22, IL-1alpha, IFN-gamma, TNF-alpha, and OSM) showed surprisingly little overlap, with the cytokine-stimulated keratinocyte expression representing only 2.5, 0.7, 1.5, 5.6, 5.0, and 1.9% of the lesional psoriatic dysregulated transcriptome, respectively. This comprehensive analysis of differentially regulated transcripts in psoriasis provides additional insight into the pathogenic mechanisms involved and emphasizes the need for more complex yet tractable experimental models of psoriasis.
Journal of Investigative Dermatology 03/2010; 130(7):1829-40. · 6.31 Impact Factor
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Josée Dupuis,
Claudia Langenberg,
Inga Prokopenko,
Richa Saxena,
Nicole Soranzo,
Anne U Jackson,
Eleanor Wheeler,
Nicole L Glazer,
Nabila Bouatia-Naji,
Anna L Gloyn, [......],
Nicholas J Wareham,
Robert Sladek,
Philippe Froguel,
Richard M Watanabe,
James B Meigs,
Leif Groop,
Michael Boehnke,
Mark I McCarthy,
Jose C Florez,
Inês Barroso
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ABSTRACT: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Nature Genetics 02/2010; 42(2):105-16. · 35.53 Impact Factor
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Toshiko Tanaka,
Cindy N Roy,
Wenliang Yao,
Amy Matteini,
Richard D Semba,
Dan Arking,
Jeremy D Walston,
Linda P Fried,
Andrew Singleton,
Jack Guralnik, Gonçalo R Abecasis,
Stefania Bandinelli,
Dan L Longo,
Luigi Ferrucci
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ABSTRACT: To investigate genetic variants that affect iron concentrations in persons not affected by overt genetic disorders of iron metabolism, a genome-wide association study was conducted in the InCHIANTI Study (N = 1206) and the Baltimore Longitudinal Study of Aging (N = 713). The top 2 single-nucleotide polymorphisms were examined for replication in the Women's Health and Aging Study (WHAS) I and II (N = 569). The single-nucleotide polymorphism most strongly associated with lower serum iron concentration was rs4820268 (P = 5.12 x 10(-9)), located in exon 13 of the transmembrane protease serine 6 (TMPRSS6) gene, an enzyme that promotes iron absorption and recycling by inhibiting hepcidin antimicrobial peptide transcription. The allele associated with lower iron concentrations was also associated with lower hemoglobin levels, smaller red cells, and more variability in red cell size (high red blood cell distribution width). Our results confirm the association of TMPRSS6 variants with iron level and provide further evidence of association with other anemia-related phenotypes.
Blood 10/2009; 115(1):94-6. · 9.90 Impact Factor
