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ABSTRACT: Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14-20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances.
Epigenetics: official journal of the DNA Methylation Society 04/2013; 8(5). · 4.58 Impact Factor
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ABSTRACT: Objective
This study examined the genetic and environmental contributions to the individual differences in blood pressure (BP) levels and underlying hemodynamic characteristics at rest and during mental challenge tasks in a large twin cohort of youth. Including both European American and African American twins further allowed examination of potential ethnic differences.Methods
We studied cardiovascular reactivity to two stressors (car-driving simulation and a social stressor interview) in 308 European American and 223 African American twin pairs including monozygotic twin pairs and same-sex as well as opposite-sex dizygotic twin pairs (mean [standard deviation] age = 14.7 [3.1]). Variables included systolic and diastolic BP, heart rate, stroke volume, cardiac output, and total peripheral resistance.ResultsHeritability indices for levels at rest and during stress were high (31%-73%) and comparable between ethnic groups. A common genetic factor accounted for both resting and stress levels explaining 23% to 58% of the total variance. The increases in heritability indices for BP and heart rate from rest to stress are mostly explained by newly emerging genetic influences on the added stress component. Indices for hemodynamic variables remained stable from rest to stress owing to a simultaneous decrease in genetic and environmental variances.Conclusions
Cardiovascular measures obtained during rest and stress show substantial heritability that is comparable between individuals of African and European descent. Most of the variance in both resting and stress levels is explained by common genetic factors, although other genetic factors that only contribute to cardiovascular levels during stress are also important.
Psychosomatic Medicine 04/2013; · 3.97 Impact Factor
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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
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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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Xiaojing Xu,
Xiuhua Ding,
Xinyan Zhang,
Shaoyong Su,
Frank A Treiber,
Robert Vlietinck,
Robert Fagard,
Catherine Derom,
Marij Gielen,
Ruth J F Loos, Harold Snieder,
Xiaoling Wang
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ABSTRACT: OBJECTIVES:: Blood pressure variability (BPV) and its reduction in response to antihypertensive treatment are predictors of clinical outcomes; however, little is known about its heritability. In this study, we examined the relative influence of genetic and environmental sources of variance of BPV and the extent to which it may depend on race or sex in young twins. METHODS:: Twins were enrolled from two studies. One study included 703 white twins (308 pairs and 87 singletons) aged 18-34 years, whereas another study included 242 white twins (108 pairs and 26 singletons) and 188 black twins (79 pairs and 30 singletons) aged 12-30 years. BPV was calculated from 24-h ambulatory blood pressure recording. RESULTS:: Twin modeling showed similar results in the separate analysis in both twin studies and in the meta-analysis. Familial aggregation was identified for SBP variability (SBPV) and DBP variability (DBPV) with genetic factors and common environmental factors together accounting for 18-40% and 23-31% of the total variance of SBPV and DBPV, respectively. Unique environmental factors were the largest contributor explaining up to 82-77% of the total variance of SBPV and DBPV. No sex or race difference in BPV variance components was observed. The results remained the same after adjustment for 24-h blood pressure levels. CONCLUSIONS:: The variance in BPV is predominantly determined by unique environment in youth and young adults, although familial aggregation due to additive genetic and/or common environment influences was also identified explaining about 25% of the variance in BPV.
Journal of hypertension 04/2013; 31(4):690-697. · 4.02 Impact Factor
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Santhi K Ganesh,
Vinicius Tragante,
Wei Guo,
Yiran Guo,
Matthew B Lanktree,
Erin N Smith,
Toby Johnson,
Berta Almoguera Castillo,
John Barnard,
Jens Baumert, [......],
Pim van der Harst,
Yvonne T van der Schouw,
Nilesh J Samani,
Andrew D Johnson,
Patricia B Munroe,
Paul I W de Bakker,
Xiaofeng Zhu,
Daniel Levy,
Brendan J Keating,
Folkert W Asselbergs
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ABSTRACT: Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 single nucleotide polymorphisms (SNPs) that capture variation in ∼2,100 candidate genes for cardiovascular phenotypes in 61,619 individuals of European ancestry from cohort studies in the US and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed ten previously known loci associated with SBP, DBP, MAP, or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P value<2.4 x 10(-6)). We then replicated these associations in an independent set of 65,886 individuals of European ancestry. Findings from eQTL analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease, left ventricular hypertrophy, or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
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Xiaoling Wang,
Bonita Falkner,
Haidong Zhu,
Huidong Shi,
Shaoyong Su,
Xiaojing Xu,
Ashok Kumar Sharma,
Yanbin Dong,
Frank Treiber,
Bernard Gutin,
Gregory Harshfield, Harold Snieder
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ABSTRACT: There is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension.
We conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14-23 years and performed validation of the most significant CpG sites in 2 genes in an independent sample of 36 hypertensive cases and 60 normotensive controls aged 14-30 years. Validation of the CpG sites in the SULF1 gene was further conducted in a second replication sample of 36 hypertensive cases and 34 controls aged 15.8-40 years. A CpG site in the SULF1 gene showed higher methylation levels in cases than in healthy controls in the genome-wide step (p = 6.2×10(-5)), which was confirmed in the validation step (p = 0.011) for subjects ≤30 years old but was not significant for subjects of all ages combined (p = 0.095).
The identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension. The age dependency of the effect further suggests complexity of epigenetic regulation in this age-related disease.
PLoS ONE 01/2013; 8(1):e53938. · 4.09 Impact Factor
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Anna Köttgen,
Eva Albrecht,
Alexander Teumer,
Veronique Vitart,
Jan Krumsiek,
Claudia Hundertmark,
Giorgio Pistis,
Daniela Ruggiero,
Conall M O'Seaghdha,
Toomas Haller, [......],
Nicole Soranzo,
Daniela Toniolo,
Daniel I Chasman,
Olli Raitakari,
W H Linda Kao,
Marina Ciullo,
Caroline S Fox,
Mark Caulfield,
Murielle Bochud,
Christian Gieger
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ABSTRACT: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Nature genetics. 01/2013; 45(2):145-54.
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Anna Köttgen,
Eva Albrecht,
Alexander Teumer,
Veronique Vitart,
Jan Krumsiek,
Claudia Hundertmark,
Giorgio Pistis,
Daniela Ruggiero,
Conall M O'Seaghdha,
Toomas Haller, [......],
Nicole Soranzo,
Daniela Toniolo,
Daniel I Chasman,
Olli Raitakari,
W H Linda Kao,
Marina Ciullo,
Caroline S Fox,
Mark Caulfield,
Murielle Bochud,
Christian Gieger
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ABSTRACT: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Nature Genetics 12/2012; · 35.53 Impact Factor
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ABSTRACT: OBJECTIVES: To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency-related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach. STUDY DESIGN: We performed a genome-wide methylation scan using the Illumina HumanMethylation 27 BeadChip on leukocyte DNA of 11 cases of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ≤ 25 nmol/L) and 11 age-matched controls ([25(OH)D] > 75 nmol/L); the subjects were African American normal-weight (body mass index <85th percentile) males aged 14-19 years. The Limma package was used to analyze each CpG site for differential methylation between cases and controls. To correct for multiple testing, the set of raw P values were converted to false discovery rates (FDRs). We also compared our findings with the recent data from Genome-Wide Association Studies of circulating 25(OH)D levels and then performed a permutation test to examine whether the "double hit" genes were randomly enriched. RESULTS: A total of 79 CpG sites achieved raw P < .001. Of the 79 CpG sites, 2 CpG sites survived multiple testing: cg16317961 (raw P = 3.5 × 10(-6), FDR = 0.078, in MAPRE2) and cg04623955 (raw P = 5.9 × 10(-6), FDR = 0.078, in DIO3). Furthermore, 3 out of the 4 genes previously identified in the 2 Genome-Wide Association Studies were also significant at the methylation level (DHCR7: cg07487535, P = .015 and cg10763288, P = .017; CYP2R1: cg25454890, P = .040; CYP24A1: cg18956481, P = .022), reflecting significant enrichment (P = .0098). CONCLUSION: Severe vitamin D deficiency is associated with methylation changes in leukocyte DNA. The genomic and epigenomic approach reinforce the crucial roles played by the DHCR7, CYP2R1, and CYP24A1 genes in vitamin D metabolism.
The Journal of pediatrics 12/2012; · 4.02 Impact Factor
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Pim van der Harst,
Weihua Zhang,
Irene Mateo Leach,
Augusto Rendon,
Niek Verweij,
Joban Sehmi,
Dirk S Paul,
Ulrich Elling,
Hooman Allayee,
Xinzhong Li, [......],
Manuel A Ferreira,
Serena Sanna,
Manuela Uda,
Andrew A Hicks,
Josef Martin Penninger,
Christian Gieger,
Jaspal S Kooner,
Willem H Ouwehand,
Nicole Soranzo,
John C Chambers
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ABSTRACT: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Nature 12/2012; · 36.28 Impact Factor
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ABSTRACT: The Twin Interdisciplinary Neuroticism Study (TWINS) is a three-wave study including >800 twin pairs from the northern part of the Netherlands. The aim of the study is to unravel why neuroticism reflects vulnerability to mental disorders. In this study, we focus on possible mechanisms underlying this vulnerability and their genetic and environmental origins. In total, 125 female twin pairs visited our psychophysiological laboratory. From these twin pairs DNA was isolated and both candidate gene and genome-wide genotyping were conducted. Future work includes studies of candidate genes. The study also participates in several meta-genome-wide association study (GWAS) consortia.
Twin Research and Human Genetics 11/2012; · 1.70 Impact Factor
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ABSTRACT: The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined.We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality.Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses.After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18).In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.
Cardiovascular Diabetology 11/2012; 11(1):138. · 3.35 Impact Factor
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Nora Franceschini,
Frank J A van Rooij,
Bram P Prins,
Mary F Feitosa,
Mahir Karakas,
John H Eckfeldt,
Aaron R Folsom,
Jeffrey Kopp,
Ahmad Vaez,
Jeanette S Andrews, [......],
Alan F Wright,
Qingyu Wu,
Yongmei Liu,
Nancy S Jenny,
Kari E North,
Janine F Felix,
Behrooz Z Alizadeh,
L Adrienne Cupples,
John R B Perry,
Andrew P Morris
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ABSTRACT: Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.
The American Journal of Human Genetics 09/2012; 91(4):744-753. · 10.60 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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ABSTRACT: Genetic and environmental contributions to urinary excretion rates of norepinephrine (U(NE)V) and epinephrine (U(E)V) and their association with blood pressure (BP) were investigated in 91 African American (mean age, 17.3±2.6 years) and 101 European American (mean age, 18.7±3.4 years) mono- and di-zygotic twins. Genetic modeling was performed using Mx software. U(NE)V (1.9±1.3 μg h(-1)) and U(E)V (0.2±0.2 μg h(-1)) were highly correlated (r=0.81, P<0.001). Significant heritabilities for U(NE)V (0.68) and U(E)V (0.74) without ethnic and gender effects were observed. The genetic correlation between U(NE)V and U(E)V was 0.86. There was no clear pattern of correlations for U(NE)V and U(E)V with BP measures in European Americans, but African Americans showed some inverse correlations of moderate size. Measurements of U(NE)V and U(E)V provide a viable method for the study of sympathetic tone and are substantially heritable.Hypertension Research advance online publication, 12 July 2012; doi:10.1038/hr.2012.104.
Hypertension Research 07/2012; · 2.58 Impact Factor
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Paul G Sanfilippo,
Christopher J Hammond,
Sandra E Staffieri,
Lisa S Kearns,
S H Melissa Liew,
Julie M Barbour,
Alex W Hewitt,
Dongliang Ge, Harold Snieder,
Jane R Mackinnon,
Shayne A Brown,
Birgit Lorenz,
Tim D Spector,
Nicholas G Martin,
Jeremy B Wilmer,
David A Mackey
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ABSTRACT: Strabismus represents a complex oculomotor disorder characterized by the deviation of one or both eyes and poor vision. A more sophisticated understanding of the genetic liability of strabismus is required to guide searches for associated molecular variants. In this classical twin study of 1,462 twin pairs, we examined the relative influence of genes and environment in comitant strabismus, and the degree to which these influences can be explained by factors in common with refractive error. Participants were examined for the presence of latent ('phoria') and manifest ('tropia') strabismus using cover-uncover and alternate cover tests. Two phenotypes were distinguished: eso-deviation (esophoria and esotropia) and exo-deviation (exophoria and exotropia). Structural equation modeling was subsequently employed to partition the observed phenotypic variation in the twin data into specific variance components. The prevalence of eso-deviation and exo-deviation was 8.6% and 20.7%, respectively. For eso-deviation, the polychoric correlation was significantly greater in monozygotic (MZ) (r = 0.65) compared to dizygotic (DZ) twin pairs (r = 0.33), suggesting a genetic role (p = .003). There was no significant difference in polychoric correlation between MZ (r = 0.55) and DZ twin pairs (r = 0.53) for exo-deviation (p = .86), implying that genetic factors do not play a significant role in the etiology of exo-deviation. The heritability of an eso-deviation was 0.64 (95% CI 0.50-0.75). The additive genetic correlation for eso-deviation and refractive error was 0.13 and the bivariate heritability (i.e., shared variance) was less than 1%, suggesting negligible shared genetic effect. This study documents a substantial heritability of 64% for eso-deviation, yet no corresponding heritability for exo-deviation, suggesting that the genetic contribution to strabismus may be specific to eso-deviation. Future studies are now needed to identify the genes associated with eso-deviation and unravel their mechanisms of action.
Twin Research and Human Genetics 06/2012; 15(5):624-30. · 1.70 Impact Factor
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ABSTRACT: Previous epidemiologic studies have evaluated the use of immunological markers as possible tools for measuring ageing and predicting age-related pathology. The importance of both genetic and environmental influences in regulation of these markers has been emphasized. In order to further evaluate this relationship, the present study aims to investigate the relative influence of genetic and environmental factors on four key cytokines involved in the human immune response (Interleukin (IL)-1β, IL-6, IL-10 and Tumor Necrosis Factor (TNF)-α). In addition, the role of age as a possible moderator on these influences was evaluated.
The study was conducted in 1603 females from the Twins UK registry, with mean age ± SD of 60.4 ± 12.2 years, including 863 monozygotic twins (385 pairs and 93 singletons) and 740 dizygotic twins (321 pairs and 98 singletons). Heritability was estimated using structural equation modeling. The role of age as a moderator was evaluated using gene-age interaction models.
Heritabilities were moderate for IL-1β (range: 0.27-0.32) and IL-10 (0.30) and low for IL-6 (range: 0.15-0.16) and TNF-α (range: 0.17-0.23). For IL-1β, heritability declines with age due to an increase in unique environmental factors. For TNF-α, heritability increases with age due to a decrease in unique environmental factors.
The current findings illustrate the importance of genetic and environmental influences on four cytokines involved in the human immune response. For two of these there is evidence that heritability changes with age owing to changes in environmental factors unique to the individual.
Cytokine 06/2012; 60(1):108-13. · 3.02 Impact Factor
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Yalda Jamshidi,
Ilja M Nolte,
Chrysoula Dalageorgou,
Dongling Zheng,
Toby Johnson,
Rachel Bastiaenen,
Suzanne Ruddy,
Daniel Talbott,
Kris J Norris, Harold Snieder,
Alfred L George,
Vanessa Marshall,
Saad Shakir,
Prince J Kannankeril,
Patricia B Munroe,
A John Camm,
Steve Jeffery,
Dan M Roden,
Elijah R Behr
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ABSTRACT: This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS).
Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS.
This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study.
The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4)).
These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.
Journal of the American College of Cardiology 05/2012; 60(9):841-50. · 14.16 Impact Factor
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ABSTRACT: Genome-wide association (GWA) studies on coronary artery disease (CAD) have been very successful, identifying a total of 32 susceptibility loci so far. Although these loci have provided valuable insights into the etiology of CAD, their cumulative effect explains surprisingly little of the total CAD heritability. In this review, we first highlight and describe the type of genetic variants potentially underlying the missing heritability of CAD: single nucleotide polymorphisms (SNPs) or structural variants, each of which may either be common or rare. Although finding missing heritability is important, we further argue in this review that it constitutes only a first step towards a fuller understanding of the etiology of CAD development. To close the gap between the genotype and phenotype, we propose a systems genetics approach in the post-GWA study era. This approach that integrates genetic, epigenetic, transcriptomic, proteomic, metabolic and intermediate outcome variables has potential to significantly aid the understanding of CAD etiology.
Atherosclerosis 05/2012; 225(1):1-10. · 3.79 Impact Factor
