-
Benjamin F Voight,
Hyun Min Kang,
Jun Ding,
Cameron D Palmer,
Carlo Sidore,
Peter S Chines,
Noël P Burtt,
Christian Fuchsberger,
Yanming Li,
Jeanette Erdmann, [......],
Patricia B Munroe,
Christopher Newton-Cheh,
Arne Pfeufer,
Nilesh J Samani,
Heribert Schunkert,
Joel N Hirschhorn,
David Altshuler,
Mark I McCarthy,
Gonçalo R Abecasis,
Michael Boehnke
PLoS Genetics 04/2013; 9(4). · 8.69 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
-
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
[show abstract]
[hide abstract]
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.
-
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
[show abstract]
[hide abstract]
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
-
Robert A Scott,
Vasiliki Lagou,
Ryan P Welch,
Eleanor Wheeler,
May E Montasser,
Jian'an Luan,
Reedik Mägi,
Rona J Strawbridge,
Emil Rehnberg,
Stefan Gustafsson, [......],
Nabila Bouatia-Naji,
Mark I McCarthy,
Paul W Franks,
James B Meigs,
Tanya M Teslovich,
Jose C Florez,
Claudia Langenberg,
Erik Ingelsson,
Inga Prokopenko,
Inês Barroso
[show abstract]
[hide abstract]
ABSTRACT: Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
Nature Genetics 08/2012; 44(9):991-1005. · 35.53 Impact Factor
-
Benjamin F Voight,
Hyun Min Kang,
Jun Ding,
Cameron D Palmer,
Carlo Sidore,
Peter S Chines,
Noël P Burtt,
Christian Fuchsberger,
Yanming Li,
Jeanette Erdmann, [......],
Patricia B Munroe,
Christopher Newton-Cheh,
Arne Pfeufer,
Nilesh J Samani,
Heribert Schunkert,
Joel N Hirschhorn,
David Altshuler,
Mark I McCarthy,
Gonçalo R Abecasis,
Michael Boehnke
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
PLoS Genetics 08/2012; 8(8):e1002793. · 8.69 Impact Factor
-
Serena Sanna,
Bingshan Li,
Antonella Mulas,
Carlo Sidore,
Hyun M Kang,
Anne U Jackson,
Maria Grazia Piras,
Gianluca Usala,
Giuseppe Maninchedda,
Alessandro Sassu, [......],
Kristian Hveem,
Jaakko Tuomilehto,
Timo A Lakka,
Rainer Rauramaa,
Michael Boehnke,
Francesco Cucca,
Manuela Uda,
David Schlessinger, Ramaiah Nagaraja,
Gonçalo R Abecasis
[show abstract]
[hide abstract]
ABSTRACT: Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
PLoS Genetics 07/2011; 7(7):e1002198. · 8.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Placenta-specific 1 (PLAC1) is a recently described X-linked gene with expression restricted primarily to cells derived from trophoblast lineage during embryonic development. PLAC1 localizes to a region of the X chromosome thought to be important in placental development although its role in this process has not been defined. This review summarizes our current understanding of its expression, regulation, and function. PLAC1 is expressed throughout human pregnancy by the differentiated trophoblast and localizes to membranous structures in the syncytiotrophoblast, including the microvillous plasma membrane surface. Recent studies have demonstrated that PLAC1 is also expressed by a wide variety of human cancers. Studies of the PLAC1 promoter regions indicate that its expression in both normal placenta and cancer cells is driven by specific interactions involving a combination of transcription factors. Although functional insight into PLAC1 in the normal trophoblast is lacking, preliminary studies suggest that cancer-derived PLAC1 has the potential to promote tumor growth and function. In addition, it also appears to elicit a specific immunologic response that may influence survival in some cancer patients, suggesting that it may provide a therapeutic target for the treatment of some cancers. We also discuss a potential role for PLAC1 as a biomarker predictive of specific pregnancy complications, such as preeclampsia.
Prenatal Diagnosis 06/2010; 30(6):497-502. · 2.11 Impact Factor
-
Akira Nishiyama,
Li Xin,
Alexei A Sharov,
Marshall Thomas,
Gregory Mowrer,
Emily Meyers,
Yulan Piao,
Samir Mehta,
Sarah Yee,
Yuhki Nakatake, [......],
Sung-Lim Lee,
Manuela Monti,
Ilaria Stanghellini,
Md Nurul Islam, Ramaiah Nagaraja,
Ilya Goldberg,
Weidong Wang,
Dan L Longo,
David Schlessinger,
Minoru S H Ko
[show abstract]
[hide abstract]
ABSTRACT: To examine transcription factor (TF) network(s), we created mouse ESC lines, in each of which 1 of 50 TFs tagged with a FLAG moiety is inserted into a ubiquitously controllable tetracycline-repressible locus. Of the 50 TFs, Cdx2 provoked the most extensive transcriptome perturbation in ESCs, followed by Esx1, Sox9, Tcf3, Klf4, and Gata3. ChIP-Seq revealed that CDX2 binds to promoters of upregulated target genes. By contrast, genes downregulated by CDX2 did not show CDX2 binding but were enriched with binding sites for POU5F1, SOX2, and NANOG. Genes with binding sites for these core TFs were also downregulated by the induction of at least 15 other TFs, suggesting a common initial step for ESC differentiation mediated by interference with the binding of core TFs to their target genes. These ESC lines provide a fundamental resource to study biological networks in ESCs and mice.
Cell stem cell 10/2009; 5(4):420-33. · 23.56 Impact Factor
-
Melanie Kolz,
Toby Johnson,
Serena Sanna,
Alexander Teumer,
Veronique Vitart,
Markus Perola,
Massimo Mangino,
Eva Albrecht,
Chris Wallace,
Martin Farrall, [......],
Angela Doering,
H-Erich Wichmann,
Tim D Spector,
Leena Peltonen,
Henry Völzke, Ramaiah Nagaraja,
Peter Vollenweider,
Mark Caulfield,
Thomas Illig,
Christian Gieger
[show abstract]
[hide abstract]
ABSTRACT: Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
PLoS Genetics 07/2009; 5(6):e1000504. · 8.69 Impact Factor
-
Kirill V Tarasov,
Serena Sanna,
Angelo Scuteri,
James B Strait,
Marco Orrù,
Afshin Parsa,
Ping-I Lin,
Andrea Maschio,
Sandra Lai,
Maria Grazia Piras, [......],
Jeffrey R O'Connell,
David Schlessinger,
Antonio Cao, Ramaiah Nagaraja,
Braxton D Mitchell,
Gonçalo R Abecasis,
Alan R Shuldiner,
Manuela Uda,
Edward G Lakatta,
Samer S Najjar
[show abstract]
[hide abstract]
ABSTRACT: Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV.
The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age(2), and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the COL4A1 gene on chromosome 13 and SNP rs1495448 in the MAGI1 gene on chromosome 3 were successfully replicated (P=7.08 x 10(-7) and P=1.06 x 10(-5), respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (P=0.02) in an independent population, the Old-Order Amish, leading to an overall P=5.16 x 10(-8).
A genome-wide association study identified a SNP in the COL4A1 gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness.
Circulation Cardiovascular Genetics 04/2009; 2(2):151-8. · 6.11 Impact Factor
-
Ruth J F Loos,
Cecilia M Lindgren,
Shengxu Li,
Eleanor Wheeler,
Jing Hua Zhao,
Inga Prokopenko,
Michael Inouye,
Rachel M Freathy,
Antony P Attwood,
Jacques S Beckmann, [......],
Serena Sanna,
Goncalo R Abecasis,
Giuseppe Albai, Ramaiah Nagaraja,
David Schlessinger,
Anne U Jackson,
Jaakko Tuomilehto,
Francis S Collins,
Michael Boehnke,
Karen L Mohlke
[show abstract]
[hide abstract]
ABSTRACT: To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
Nature Genetics 07/2008; 40(6):768-75. · 35.53 Impact Factor
-
Lisette Arnaud-Lopez,
Gianluca Usala,
Graziano Ceresini,
Braxton D Mitchell,
Maria Grazia Pilia,
Maria Grazia Piras,
Natascia Sestu,
Andrea Maschio,
Fabio Busonero,
Giuseppe Albai, [......],
Alessia Prinzis,
Stefano Mariotti,
Alan R Shuldiner,
Antonio Cao,
David Schlessinger,
Manuela Uda,
Gonçalo R Abecasis, Ramaiah Nagaraja,
Serena Sanna,
Silvia Naitza
[show abstract]
[hide abstract]
ABSTRACT: Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.
The American Journal of Human Genetics 07/2008; 82(6):1270-80. · 10.60 Impact Factor
-
Cristen J Willer,
Serena Sanna,
Anne U Jackson,
Angelo Scuteri,
Lori L Bonnycastle,
Robert Clarke,
Simon C Heath,
Nicholas J Timpson,
Samer S Najjar,
Heather M Stringham, [......],
Manuela Uda,
Jaakko Tuomilehto,
Antonio Cao,
Francis S Collins,
Edward Lakatta,
G Mark Lathrop,
Michael Boehnke,
David Schlessinger,
Karen L Mohlke,
Gonçalo R Abecasis
[show abstract]
[hide abstract]
ABSTRACT: To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
Nature Genetics 03/2008; 40(2):161-9. · 35.53 Impact Factor
-
Manuela Uda,
Renzo Galanello,
Serena Sanna,
Guillaume Lettre,
Vijay G. Sankaran,
Weimin Chen,
Gianluca Usala,
Fabio Busonero,
Andrea Maschio,
Giuseppe Albai, [......],
Lucia Perseu,
Stefania Satta,
Maria Dolores Cipollina,
Carla Sollaino,
Paolo Moi,
Joel N. Hirschhorn,
Stuart H. Orkin,
Gonçalo R. Abecasis,
David Schlessinger,
Antonio Cao
[show abstract]
[hide abstract]
ABSTRACT: β-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought
of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF)
is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this
heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and
association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP
rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10−35). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening
for β-thalassemia, and patients with attenuated forms of β-thalassemia vs. those with thalassemia major. We also show that
the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the β-thalassemia phenotype, and it is likely
they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms
of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for β-thalassemia
and sickle cell anemia.
Proceedings of the National Academy of Sciences 02/2008; 105(5):1620-1625. · 9.68 Impact Factor
-
Serena Sanna,
Anne U Jackson, Ramaiah Nagaraja,
Cristen J Willer,
Wei-Min Chen,
Lori L Bonnycastle,
Haiqing Shen,
Nicholas Timpson,
Guillaume Lettre,
Gianluca Usala, [......],
Joel N Hirschhorn,
Alan R Shuldiner,
David Schlessinger,
Francis S Collins,
George Davey Smith,
Eric Boerwinkle,
Antonio Cao,
Michael Boehnke,
Gonçalo R Abecasis,
Karen L Mohlke
[show abstract]
[hide abstract]
ABSTRACT: Identifying genetic variants that influence human height will advance our understanding of skeletal growth and development. Several rare genetic variants have been convincingly and reproducibly associated with height in mendelian syndromes, and common variants in the transcription factor gene HMGA2 are associated with variation in height in the general population. Here we report genome-wide association analyses, using genotyped and imputed markers, of 6,669 individuals from Finland and Sardinia, and follow-up analyses in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated locus GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm (overall P < 10(-15)). Our results indicate that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.
Nature Genetics 02/2008; 40(2):198-203. · 35.53 Impact Factor
-
Manuela Uda,
Renzo Galanello,
Serena Sanna,
Guillaume Lettre,
Vijay G Sankaran,
Weimin Chen,
Gianluca Usala,
Fabio Busonero,
Andrea Maschio,
Giuseppe Albai, [......],
Lucia Perseu,
Stefania Satta,
Maria Dolores Cipollina,
Carla Sollaino,
Paolo Moi,
Joel N Hirschhorn,
Stuart H Orkin,
Gonçalo R Abecasis,
David Schlessinger,
Antonio Cao
[show abstract]
[hide abstract]
ABSTRACT: beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.
Proceedings of the National Academy of Sciences 02/2008; 105(5):1620-5. · 9.68 Impact Factor
-
Siguang Li,
Serena Sanna,
Andrea Maschio,
Fabio Busonero,
Gianluca Usala,
Antonella Mulas,
Sandra Lai,
Mariano Dei,
Marco Orrù,
Giuseppe Albai, [......],
Samer S Najjar,
Jack Guralnik,
Silvia Naitza,
Laura Crisponi,
Antonio Cao,
Gonçalo Abecasis,
Luigi Ferrucci,
Manuela Uda,
Wei-Min Chen, Ramaiah Nagaraja
[show abstract]
[hide abstract]
ABSTRACT: High serum uric acid levels elevate pro-inflammatory-state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 x 10(-16)), along with eight others (p = 7.75 x 10(-16) to 6.05 x 10(-11)). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values.
PLoS Genetics 12/2007; 3(11):e194. · 8.69 Impact Factor
-
Eiji Nakashima,
Joseph R. Tran,
Tim J.M. Welting,
Ger J.M. Pruijn,
Yuichiro Hirose,
Gen Nishimura,
Hirofumi Ohashi,
Shepherd H. Schurman,
Jun Cheng,
Fabio Candotti, Ramaiah Nagaraja,
Shiro Ikegawa,
David Schlessinger
[show abstract]
[hide abstract]
ABSTRACT: Cartilage hair hypoplasia (CHH; MIM 250250) is an autosomal recessive disease with diverse clinical manifestations. It is caused by mutations in RMRP gene, the RNA component of the ribonucleoprotein complex RNase MRP. Mutations in RMRP have been found in patients in the core promoter region or in the transcribed region, but the pathogenetic effect of the mutations is unclear. Real-time PCR assays confirmed that both promoter (c.−16_−1 dup and c.−15_+2 dup) and transcribed mutations (c.168G > A and c.218A > G) lower the expression level of RMRP. Experiments with 5′RACE, showed that the reduced transcription in the promoter mutants was accompanied by shifting of the transcription initiation sites to nucleotides 5′-upstream of the authentic site. Low levels of RMRP expression levels with transcript mutations were also seen when constructs encoding the wild-type and mutant genes were transfected into cultured cells. The reduced transcription was correlated with greater instability of mutant RMRP transcripts compared to controls. A comparable reduction was seen when a mouse gene containing the c.70A > G mutation (the major mutation in humans with CHH) was introduced into ES cells in place of one of the wild-type alleles. The low expression level of the c.70A > G Rmrp RNA was confirmed by expression assays into cultured cells, and was again correlated with RNA instability. Our results indicate that a loss of mutant RNA transcripts is a critical feature of pathogenesis. © 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 11/2007; 143A(22):2675 - 2681. · 2.39 Impact Factor
-
Eiji Nakashima,
Joseph R Tran,
Tim J M Welting,
Ger J M Pruijn,
Yuichiro Hirose,
Gen Nishimura,
Hirofumi Ohashi,
Shepherd H Schurman,
Jun Cheng,
Fabio Candotti, Ramaiah Nagaraja,
Shiro Ikegawa,
David Schlessinger
[show abstract]
[hide abstract]
ABSTRACT: Cartilage hair hypoplasia (CHH; MIM 250250) is an autosomal recessive disease with diverse clinical manifestations. It is caused by mutations in RMRP gene, the RNA component of the ribonucleoprotein complex RNase MRP. Mutations in RMRP have been found in patients in the core promoter region or in the transcribed region, but the pathogenetic effect of the mutations is unclear. Real-time PCR assays confirmed that both promoter (c.-16_-1 dup and c.-15_+2 dup) and transcribed mutations (c.168G > A and c.218A > G) lower the expression level of RMRP. Experiments with 5'RACE, showed that the reduced transcription in the promoter mutants was accompanied by shifting of the transcription initiation sites to nucleotides 5'-upstream of the authentic site. Low levels of RMRP expression levels with transcript mutations were also seen when constructs encoding the wild-type and mutant genes were transfected into cultured cells. The reduced transcription was correlated with greater instability of mutant RMRP transcripts compared to controls. A comparable reduction was seen when a mouse gene containing the c.70A > G mutation (the major mutation in humans with CHH) was introduced into ES cells in place of one of the wild-type alleles. The low expression level of the c.70A > G Rmrp RNA was confirmed by expression assays into cultured cells, and was again correlated with RNA instability. Our results indicate that a loss of mutant RNA transcripts is a critical feature of pathogenesis.
American Journal of Medical Genetics Part A 11/2007; 143A(22):2675-81. · 2.39 Impact Factor
