Showing papers by "Daniel I. Chasman published in 2013"
Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2 +316 more•Institutions (87)
TL;DR: It is found 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.
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.
2,585 citations
TL;DR: It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.
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.
817 citations
TL;DR: 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.
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.
633 citations
TL;DR: 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 finds 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.
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.
576 citations
01 Jan 2013
TL;DR: In this article, the authors 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).
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.
494 citations
01 Jan 2013
478 citations
Joshua C. Randall1, Joshua C. Randall2, Thomas W. Winkler3, Zoltán Kutalik4 +305 more•Institutions (89)
TL;DR: The value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits is demonstrated, with no evidence for genetic effects with opposite directions in men versus women.
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
402 citations
Montserrat Garcia-Closas, Fergus J. Couch1, Sara Lindström2, Kyriaki Michailidou3 +284 more•Institutions (82)
TL;DR: SNPs at four loci were associated with ER-negative but not ER-positive breast cancer (P > 0.05), providing further evidence for distinct etiological pathways associated with invasive ER- positive and ER- negative breast cancers.
Abstract: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
402 citations
Wellcome Trust Sanger Institute1, Oslo University Hospital2, deCODE genetics3, University of Bristol4, Helsinki University Central Hospital5, Max Planck Society6, Leiden University7, QIMR Berghofer Medical Research Institute8, University of Ulm9, King's College London10, University of Oulu11, Erasmus University Rotterdam12, University of Tampere13, VU University Amsterdam14, University of Helsinki15, Wellcome Trust16, Harvard University17, Massachusetts Institute of Technology18, University of Duisburg-Essen19, Brigham and Women's Hospital20, Ludwig Maximilian University of Munich21, University of Washington22, Erasmus University Medical Center23, University of Bonn24, University of Kiel25, Technische Universität München26, National Institutes of Health27, University College London28, Broad Institute29, VU University Medical Center30, Turku University Hospital31, Imperial College London32, St George's, University of London33, University of Iceland34
TL;DR: A meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls, identified 12 loci associated with migraine susceptibility.
Abstract: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls We identified 12 loci associated with migraine susceptibility (P<5×10(-8)) Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21 Three of these loci were identified in disease subgroup analyses Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B
315 citations
Sage Bionetworks1, Duke University2, University of Chicago3, Children's Hospital Oakland Research Institute4, University of Washington5, University of Pennsylvania6, Brigham and Women's Hospital7, Vanderbilt University Medical Center8, Los Angeles Biomedical Research Institute9, Clinical Trial Service Unit10
TL;DR: GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility tostatin-induced myopathy.
Abstract: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 060) Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy
209 citations
National Institutes of Health1, Boston University2, Erasmus University Rotterdam3, Washington University in St. Louis4, University of Alabama at Birmingham5, Wake Forest University6, Wellcome Trust Sanger Institute7, University of Washington8, Cambridge University Hospitals NHS Foundation Trust9, University of Helsinki10, Lund University11, Harvard University12, Umeå University13, University of Cambridge14, University of Virginia15, Tufts University16, University of Turku17, University of Tampere18, University of North Carolina at Chapel Hill19, Harokopio University20, Carlos III Health Institute21, IMDEA22, Johns Hopkins University23, Cedars-Sinai Medical Center24, University of Texas Health Science Center at Houston25
TL;DR: The results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans.
Lund University1, Novo Nordisk2, Umeå University3, Harvard University4, Karolinska Institutet5, University of Eastern Finland6, University of Copenhagen7, Cambridge University Hospitals NHS Foundation Trust8, McMaster University9, University of Michigan10, University of North Carolina at Chapel Hill11, Aarhus University12, Uppsala University13, University of Southern Denmark14
TL;DR: A meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
Abstract: Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age2, sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
University of North Carolina at Chapel Hill1, University of Mississippi2, Case Western Reserve University3, Heilongjiang University4, Vanderbilt University5, National Institutes of Health6, Washington University in St. Louis7, Loyola University Chicago8, Emory University9, Icahn School of Medicine at Mount Sinai10, Johns Hopkins University11, University of Washington12, University of Virginia13, Stanford University14, University of Texas Health Science Center at Houston15, Wake Forest University16, University of Michigan17, Scripps Research Institute18, Tulane University19, University of Lausanne20, Medical College of Wisconsin21, Fred Hutchinson Cancer Research Center22, Harvard University23, University of Geneva24, Cedars-Sinai Medical Center25, Temple University26, Université de Montréal27, George Washington University28, Dartmouth College29, University of Ibadan30, Columbia University31, Tufts University32, Boston University33, University of Vermont34, Brown University35, AstraZeneca36, Broad Institute37, University of Alabama at Birmingham38, University of Western Ontario39, Northwestern University40, Hennepin County Medical Center41, Group Health Cooperative42, University of Utah43, University of California, San Francisco44, University of Pennsylvania45
TL;DR: It is suggested that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
Abstract: High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10−8) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
TL;DR: In a genome-wide meta-analysis of a population-based discovery cohort, rs838133 in FGF21 is a potential susceptibility gene for obesity and type 2 diabetes and the potential of genetic variation for determining dietary macronutrient intake is highlighted.
Abstract: Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10−5) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n = 38 360) and attained genome-wide significance in combined analysis (Pjoint = 7.9 × 10−9). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake.
Erasmus University Rotterdam1, McMaster University2, University of Washington3, Harvard University4, National Institutes of Health5, Radboud University Nijmegen6, King's College London7, University of Lausanne8, Karolinska Institutet9, VU University Amsterdam10, University of Cambridge11, Cedars-Sinai Medical Center12, University of Oxford13, University of Lübeck14, Wageningen University and Research Centre15, Glenfield Hospital16, University of Münster17, Tufts University18, University of Bergen19, Imperial College London20, University of Pennsylvania21, University of Leicester22, University of Surrey23
TL;DR: Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tH Cy concentrations and tHCy-related pathways for CAD.
TL;DR: Strong evidence from numerous studies supports a positive association between increased consumption of sugar-sweetened beverages and the risk of obesity and it is unclear whether in
Abstract: The worldwide obesity epidemic has been largely attributed to marked changes in diet and lifestyle in the last 3 decades. Strong evidence from numerous studies supports a positive association between increased consumption of sugar-sweetened beverages and the risk of obesity. It is unclear whether in
University of Michigan1, Utrecht University2, Case Western Reserve University3, University of Pennsylvania4, University of Western Ontario5, University of California, San Diego6, Queen Mary University of London7, Cleveland Clinic8, University of Maryland, Baltimore9, University of Oxford10, University of Wisconsin-Madison11, University of North Carolina at Chapel Hill12, University of Bristol13, University of Florida14, Erasmus University Rotterdam15, Heidelberg University16, University of Groningen17, Lund University18, University of Glasgow19, Medical Research Council20, University of Washington21, Columbia University22, University College London23, NHS Blood and Transplant24, Tulane University25, Harvard University26, University of Texas Health Science Center at Houston27, Merck & Co.28, University of Mississippi29, Translational Genomics Research Institute30, National Institutes of Health31, Dalhousie University32, Georgia Regents University33, Fred Hutchinson Cancer Research Center34, Boston University35, Northwestern University36, University of Amsterdam37, Ludwig Maximilian University of Munich38, Broad Institute39, VU University Amsterdam40, Medical University of Graz41, Scripps Research Institute42, Veterans Health Administration43, Johns Hopkins University44, University of Ulm45, Hannover Medical School46, Synlab Group47, Scripps Health48, Icahn School of Medicine at Mount Sinai49, Cleveland Clinic Lerner Research Institute50, Royal College of Surgeons in Ireland51, Glenfield Hospital52, University of Leicester53
TL;DR: Two novel loci associated with BP are identified and multiple previously reported associations are confirmed, extending the understanding of genes involved in BP regulation and some of which may eventually provide new targets for therapeutic intervention.
Abstract: Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). 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 ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA 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 10 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 < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) 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.
Karolinska University Hospital1, Brigham and Women's Hospital2, Erasmus University Rotterdam3, Greifswald University Hospital4, Fred Hutchinson Cancer Research Center5, University of Minnesota6, St George's, University of London7, Leiden University Medical Center8, University of Washington9, Cedars-Sinai Medical Center10, VU University Amsterdam11, University of Bristol12, University of Edinburgh13, University of Helsinki14, National Institutes of Health15, Johns Hopkins University School of Medicine16, French Institute of Health and Medical Research17, Western General Hospital18, University of Split19, Beth Israel Deaconess Medical Center20, Josip Juraj Strossmayer University of Osijek21, University of Hawaii22, University of Iowa23, University of California, Los Angeles24, Brown University25, University of Texas Health Science Center at Houston26, Northwestern University27, King's College London28, University of Leeds29, University of Vermont30, Hannover Medical School31, Wellcome Trust Centre for Human Genetics32, Mario Negri Institute for Pharmacological Research33, University of Münster34, University of Oxford35, University of Glasgow36, University College Cork37, Boston University38, University of Sydney39, Karolinska Institutet40, University of Mississippi Medical Center41, Ludwig Maximilian University of Munich42, Imperial College London43, University of Pennsylvania44, University of Cambridge45, University of Leicester46, University of Lübeck47, Harvard University48, Aix-Marseille University49, Helsinki University Central Hospital50, Wellcome Trust51, University of Ulm52, Pierre-and-Marie-Curie University53
TL;DR: Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
Abstract: Background—Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-...
TL;DR: Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF.
Abstract: Aims Atrial fibrillation (AF) is associated with adverse outcome. Whether recently discovered genetic risk markers improve AF risk prediction is unknown.
Methods and results We derived and validated a novel AF risk prediction model from 32 possible predictors in the Women's Health Study (WHS), a cohort of 20 822 women without cardiovascular disease (CVD) at baseline followed prospectively for incident AF (median: 14.5 years). We then created a genetic risk score (GRS) comprised of 12 risk alleles in nine loci and assessed model performance in the validation cohort with and without the GRS. The newly derived WHS AF risk algorithm included terms for age, weight, height, systolic blood pressure, alcohol use, and smoking (current and past). In the validation cohort, this model was well calibrated with good discrimination [C-index (95% CI) = 0.718 (0.684–0.753)] and improved all reclassification indices when compared with age alone. The addition of the genetic score to the WHS AF risk algorithm model improved the C-index [0.741 (0.709–0.774); P = 0.001], the category-less net reclassification [0.490 (0.301–0.670); P < 0.0001], and the integrated discrimination improvement [0.00526 (0.0033–0.0076); P < 0.0001]. However, there was no improvement in net reclassification into 10-year risk categories of <1, 1–5, and 5+% [0.041 (−0.044–0.12); P = 0.33].
Conclusion Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF. The addition of genetic information resulted in modest improvements in predictive accuracy that did not translate into improved reclassification into discrete AF risk categories.
University of Minnesota1, Erasmus University Rotterdam2, Harvard University3, Mayo Clinic4, French Institute of Health and Medical Research5, University of Washington6, McMaster University7, University of Bordeaux8, Group Health Cooperative9, University of Auckland10, French Alternative Energies and Atomic Energy Commission11, University of Vermont12, Lille University of Science and Technology13, Boston University14, University of Texas Health Science Center at Houston15, Cedars-Sinai Medical Center16
TL;DR: A large genome‐wide association study among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE.
Abstract: Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
King's College London1, Vita-Salute San Raffaele University2, University of Tartu3, Harvard University4, University of North Carolina at Chapel Hill5, Indiana University6, Swiss Institute of Bioinformatics7, University of Iceland8, deCODE genetics9, University of Exeter10, Boston University11, University of Washington12, Cedars-Sinai Medical Center13, National Institutes of Health14, Group Health Cooperative15, University of Lausanne16, University of Minnesota17, QIMR Berghofer Medical Research Institute18, University of Pittsburgh19, University of Cambridge20, National University of Singapore21
TL;DR: EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants, and the combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance.
Abstract: Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
TL;DR: There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1.
Thorgeir E. Thorgeirsson1, Daniel F. Gudbjartsson1, Patrick Sulem1, Søren Besenbacher2 +313 more•Institutions (90)
TL;DR: The results strongly point to a common biological basis of the regulation of theregulation of the authors' appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity, and the effect of single-nucleotide polymorphisms affecting body mass index (BMI).
Abstract: Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10−7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10−5) and CPD (P=9.3 × 10−5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
University of North Carolina at Chapel Hill1, University of Michigan2, University of Edinburgh3, University of Split4, VU University Amsterdam5, Statens Serum Institut6, Boston University7, University of Tartu8, University of Oxford9, Harvard University10, University of Queensland11, Swiss Institute of Bioinformatics12, Erasmus University Rotterdam13, University of Western Australia14, University of Lausanne15, Indiana University16, St George's, University of London17, University of Maryland, Baltimore18, Ludwig Maximilian University of Munich19, Washington University in St. Louis20, King's College London21, University of Sassari22, Memorial University of Newfoundland23, Vita-Salute San Raffaele University24, University of Minnesota25, QIMR Berghofer Medical Research Institute26, University of Exeter27, University of Helsinki28, National Research Council29, University of Cambridge30, National Institutes of Health31
TL;DR: In this paper, the associations of 95 a priori and recently identified obesity-related single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010) were estimated using meta-analytical techniques.
Abstract: Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
TL;DR: Whether circulating Lp(a) levels impact the development of VTE, its relationship to incident VTE was assessed and two common polymorphisms in the LPA gene, rs3798220 and rs10455872 may account for at least 40% of variation in Lp (a)levels.
TL;DR: In this large prospective cohort of women, genes associated with physical fitness did not modify the inverse association between physical activity and CHD risk.
Abstract: AB Purpose: Both physical activity and physical fitness are associated with decreased coronary heart disease (CHD) risk. Our objective was to determine whether genes associated with physical fitness modify the association between physical activity and CHD. Methods: We conducted a prospective cohort study among 23,016 initially healthy women in the Women's Genome Health Study. Leisure time physical activity was reported at entry and during follow-up. A total of 58 single nucleotide polymorphisms associated with physical fitness were identified from published literature and summed to create four separate genetic scores related to phenotypes of endurance, muscle strength, V[spacing dot above]O2max, and overall fitness. Results: During a median of 14.4 yr, 320 incident CHD events occurred. Increased physical activity was associated with lower CHD risk in multivariable-adjusted models (P = 0.0008). Independent of physical activity, only muscle strength genetic score was inversely associated with CHD risk (P = 0.05). There was no evidence that the inverse relation between physical activity and CHD was modified by any of the genetic scores for physical fitness. For overall fitness genetic score, the hazard ratio (HR) per 500 kcal[middle dot]wk-1 of physical activity was 0.85 (95% confidence interval [CI] = 0.72-1.00) in the highest quartile of genetic score and 0.79 (95% CI = 0.67-0.92) in the lowest quartile (P, interaction = 0.50). For V[spacing dot above]O2max genetic score, the HR was 0.86 (95% CI = 0.72-1.02) and 0.84 (95% CI = 0.72-0.98), respectively (P, interaction = 0.59). Conclusions: In this large prospective cohort of women, genes associated with physical fitness did not modify the inverse association between physical activity and CHD risk
TL;DR: A comprehensive database of genes for Mendelian kidney conditions is developed and the association between common genetic variants within these genes and kidney function in the general population is evaluated.
Abstract: Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
TL;DR: NT-proBNP concentrations that are high, but still within the reference interval, associate with reduced risk of incident diabetes in women and support a favorable role for natriuretic peptides in the prevention of T2DM.
Abstract: BACKGROUND: Animal data suggest that natriuretic peptides play an important role in energy metabolism, but prospective studies evaluating a relationship between these peptides and type 2 diabetes mellitus (T2DM) in humans are few and results are conflicting.
METHODS: We used a prospective case-cohort approach (n = 491 T2DM cases, n = 561 reference subcohort) within the Women's Health Study to evaluate baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and the risk of incident T2DM. We also tested for associations between 4 common variants in the natriuretic peptide A and B genes ( NPPA and NPPB ) and NT-proBNP concentrations (n = 458) and incident T2DM (n = 1372 cases among 22 607 women).
RESULTS: Case subjects had higher median baseline body mass index (29.4 vs 25.0 kg/m2, P < 0.001) and lower baseline median (interquartile range) NT-proBNP concentrations [46.8 ng/L (26.1–83.2) vs 66.7 ng/L (39.3–124.7), P < 0.001]. In proportional hazards models adjusting for established diabetes risk factors, women in the highest quartile of baseline NT-proBNP concentration (≥117.4 ng/L) had a 49% reduction in risk of T2DM [hazard ratio (HR) 0.51, 0.30–0.86, P = 0.01] relative to those in the lowest quartile. Two of the 4 tested variants in NPPA and NPPB (rs632793, rs198389) were associated with increased NT-proBNP concentrations and reduced risk of T2DM. For example, each copy of the minor allele of rs632793 was associated with increased NT-proBNP [β (SE) = 0.201 (0.063), P < 0.01] and decreased T2DM risk (HR 0.91, 0.84–0.989, P = 0.026).
CONCLUSIONS: NT-proBNP concentrations that are high, but still within the reference interval, associate with reduced risk of incident diabetes in women and support a favorable role for natriuretic peptides in the prevention of T2DM.
Oslo University Hospital1, Wellcome Trust Sanger Institute2, deCODE genetics3, University of Bristol4, Helsinki University Central Hospital5, Max Planck Society6, Leiden University7, QIMR Berghofer Medical Research Institute8, University of Ulm9, King's College London10, University of Oulu11, Erasmus University Rotterdam12, University of Tampere13, VU University Amsterdam14, University of Helsinki15, Wellcome Trust16, Massachusetts Institute of Technology17, Harvard University18, University of Duisburg-Essen19, Brigham and Women's Hospital20, Ludwig Maximilian University of Munich21, University of Washington22, Erasmus University Medical Center23, University of Bonn24, University of Kiel25, Technische Universität München26, National Institutes of Health27, University College London28, Broad Institute29, VU University Medical Center30, Turku University Hospital31, Imperial College London32, St George's, University of London33, University of Iceland34
TL;DR: A meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine and 95,425 population-matched controls, identifies 12 loci associated with migraine susceptibility and suggests potential functional candidate genes at four loci.
Abstract: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.
TL;DR: The member databases themselves produce regular releases, and for TIGRFAMs the number of models has increased from 1109 in release 1.0 to 1415 in release 2.0 (beginning of 2002).
Abstract: The member databases themselves produce regular releases. PRINTS produces quarterly releases with 50 new fingerprints per release, resulting in 200 additional fingerprints per annum. At InterPro’s conception Pfam had 2008 HMMs, and plan to reach a total of 5000 families by the end of 2002. In 2000 they produced 715 HMMs, in 2001 735 HMMs and aim to have produced 1700 additional HMMs by the end of 2002. For TIGRFAMs, the number of models has increased from 1109 in release 1.0 (2001) to 1415 in release 2.0 (beginning of 2002). The first release of PROSITE in 1989 contained just 60 entries, and today release 17.0 has 1501 signatures. Release 12.0 in 1994 saw the introduction of the first profiles into the releases, and since then they have produced an average of just over 100 new signatures per release (approximately per year).