-
Lindsay Fernández-Rhodes,
Ellen W Demerath,
Diana L Cousminer,
Ran Tao,
Jill G Dreyfus,
Tõnu Esko,
Albert V Smith,
Vilmundur Gudnason,
Tamara B Harris,
Lenore Launer, [......],
Lynda M Rose,
Paul M Ridker,
Charles Poole,
Joel N Hirschhorn,
Joanne M Murabito,
Daniel I Chasman,
Elisabeth Widen,
Kari E North,
Ken K Ong,
Nora Franceschini
[show abstract]
[hide abstract]
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.
American journal of epidemiology 04/2013; · 5.59 Impact Factor
-
Eleonora Porcu,
Marco Medici,
Giorgio Pistis,
Claudia B Volpato,
Scott G Wilson,
Anne R Cappola,
Steffan D Bos,
Joris Deelen,
Martin den Heijer,
Rachel M Freathy, [......],
Theo J Visser,
Bruce H R Wolffenbuttel,
Ingrid Meulenbelt,
Jerome I Rotter,
Tim D Spector,
Andrew A Hicks,
Daniela Toniolo,
Serena Sanna,
Robin P Peeters,
Silvia Naitza
[show abstract]
[hide abstract]
ABSTRACT: Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
PLoS Genetics 02/2013; 9(2):e1003266. · 8.69 Impact Factor
-
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
[show abstract]
[hide abstract]
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
-
Chunyan He,
Daniel I Chasman,
Jill Dreyfus,
Shih-Jen Hwang,
Rikje Ruiter,
Serena Sanna,
Julie E Buring,
Lindsay Fernández-Rhodes,
Nora Franceschini,
Susan E Hankinson, [......],
Greta L Splansky,
Lisette Stolk,
André G Uitterlinden,
Stephen J Chanock,
Laura Crisponi,
Ellen W Demerath,
Joanne M Murabito,
Paul M Ridker,
Bruno H Stricker,
David J Hunter
[show abstract]
[hide abstract]
ABSTRACT: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.
In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.
After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.
Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.
Breast cancer research: BCR 03/2012; 14(2):R54. · 5.24 Impact Factor
-
Lisette Stolk,
John R B Perry,
Daniel I Chasman,
Chunyan He,
Massimo Mangino,
Patrick Sulem,
Maja Barbalic,
Linda Broer,
Enda M Byrne,
Florian Ernst, [......],
Elizabeth A Streeten,
Unnur Thorsteinsdottir,
Manuela Uda,
G Uitterlinden,
Cornelia M van Duijn,
Henry,
Anna Murray,
Joanne M Murabito,
Jenny A Visser,
Kathryn L Lunetta
Nature Genetics 01/2012; 44(3):260-268. · 35.53 Impact Factor
-
Silvia Naitza, Eleonora Porcu,
Maristella Steri,
Dennis D Taub,
Antonella Mulas,
Xiang Xiao,
James Strait,
Mariano Dei,
Sandra Lai,
Fabio Busonero, [......],
Sergio Uzzau,
Paul Scheet,
Dan L Longo,
Edward Lakatta,
Gonçalo R Abecasis,
Antonio Cao,
David Schlessinger,
Manuela Uda,
Serena Sanna,
Francesco Cucca
[show abstract]
[hide abstract]
ABSTRACT: Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
PLoS Genetics 01/2012; 8(1):e1002480. · 8.69 Impact Factor
-
Lisette Stolk,
John R B Perry,
Daniel I Chasman,
Chunyan He,
Massimo Mangino,
Patrick Sulem,
Maja Barbalic,
Linda Broer,
Enda M Byrne,
Florian Ernst, [......],
Elizabeth A Streeten,
Unnur Thorsteinsdottir,
Manuela Uda,
André G Uitterlinden,
Cornelia M van Duijn,
Henry Völzke,
Anna Murray,
Joanne M Murabito,
Jenny A Visser,
Kathryn L Lunetta
[show abstract]
[hide abstract]
ABSTRACT: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
Nature Genetics 01/2012; 44(3):260-8. · 35.53 Impact Factor
-
Christian Gieger,
Aparna Radhakrishnan,
Ana Cvejic,
Weihong Tang, Eleonora Porcu,
Giorgio Pistis,
Jovana Serbanovic-Canic,
Ulrich Elling,
Alison H Goodall,
Yann Labrune, [......],
Inga Prokopenko,
Derek Stemple,
Daniela Toniolo,
Lorenz Wernisch,
Serena Sanna,
Andrew A Hicks,
Augusto Rendon,
Manuel A Ferreira,
Willem H Ouwehand,
Nicole Soranzo
[show abstract]
[hide abstract]
ABSTRACT: Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
Nature 01/2011; 480(7376):201-8. · 36.28 Impact Factor
-
Irene Pichler,
Cosetta Minelli,
Serena Sanna,
Toshiko Tanaka,
Christine Schwienbacher,
Silvia Naitza, Eleonora Porcu,
Cristian Pattaro,
Fabio Busonero,
Alessandra Zanon, [......],
Carsten Gnewuch,
Eric Schadt,
Manfred Mitterer,
David Schlessinger,
Luigi Ferrucci,
Derrick R Witcher,
Andrew A Hicks,
Günter Weiss,
Manuela Uda,
Peter P Pramstaller
[show abstract]
[hide abstract]
ABSTRACT: The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.
Human Molecular Genetics 01/2011; 20(6):1232-40. · 7.64 Impact Factor
-
Cathy E Elks,
John R B Perry,
Patrick Sulem,
Daniel I Chasman,
Nora Franceschini,
Chunyan He,
Kathryn L Lunetta,
Jenny A Visser,
Enda M Byrne,
Diana L Cousminer, [......],
Paul M Ridker,
Tim D Spector,
Elizabeth A Streeten,
Kari Stefansson,
Unnur Thorsteinsdottir,
André G Uitterlinden,
Elisabeth Widen,
Joanne M Murabito,
Ken K Ong,
Anna Murray
[show abstract]
[hide abstract]
ABSTRACT: To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
Nature Genetics 12/2010; 42(12):1077-85. · 35.53 Impact Factor
-
Nicole Soranzo,
Serena Sanna,
Eleanor Wheeler,
Christian Gieger,
Dörte Radke,
Josée Dupuis,
Nabila Bouatia-Naji,
Claudia Langenberg,
Inga Prokopenko,
Elliot Stolerman, [......],
Michael Boehnke,
Philippe Froguel,
Leif Groop,
Mark I McCarthy,
W H Linda Kao,
Jose C Florez,
Manuela Uda,
Nicholas J Wareham,
Inês Barroso,
James B Meigs
[show abstract]
[hide abstract]
ABSTRACT: Glycated hemoglobin (HbA₁(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels.
We studied associations with HbA₁(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA₁(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.
Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10⁻²⁶), HFE (rs1800562/P = 2.6 × 10⁻²⁰), TMPRSS6 (rs855791/P = 2.7 × 10⁻¹⁴), ANK1 (rs4737009/P = 6.1 × 10⁻¹²), SPTA1 (rs2779116/P = 2.8 × 10⁻⁹) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10⁻⁹), and four known HbA₁(c) loci: HK1 (rs16926246/P = 3.1 × 10⁻⁵⁴), MTNR1B (rs1387153/P = 4.0 × 10⁻¹¹), GCK (rs1799884/P = 1.5 × 10⁻²⁰) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10⁻¹⁸). We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c).
GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c).
Diabetes 12/2010; 59(12):3229-39. · 8.29 Impact Factor
-
Serena Sanna,
Maristella Pitzalis,
Magdalena Zoledziewska,
Ilenia Zara,
Carlo Sidore,
Raffaele Murru,
Michael B Whalen,
Fabio Busonero,
Andrea Maschio,
Gianna Costa, [......],
Maura Pugliatti,
Sebastiano Traccis,
Andrea Angius,
Maurizio Melis,
Giulio Rosati,
Gonçalo R Abecasis,
Manuela Uda,
Maria Giovanna Marrosu,
David Schlessinger,
Francesco Cucca
[show abstract]
[hide abstract]
ABSTRACT: A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10), OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.
Nature Genetics 06/2010; 42(6):495-7. · 35.53 Impact Factor
