排序方式: 共有8条查询结果,搜索用时 31 毫秒
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Manning AK Hivert MF Scott RA Grimsby JL Bouatia-Naji N Chen H Rybin D Liu CT Bielak LF Prokopenko I Amin N Barnes D Cadby G Hottenga JJ Ingelsson E Jackson AU Johnson T Kanoni S Ladenvall C Lagou V Lahti J Lecoeur C Liu Y Martinez-Larrad MT Montasser ME Navarro P Perry JR Rasmussen-Torvik LJ Salo P Sattar N Shungin D Strawbridge RJ Tanaka T van Duijn CM An P de Andrade M Andrews JS Aspelund T Atalay M Aulchenko Y Balkau B Bandinelli S Beckmann JS Beilby JP Bellis C Bergman RN Blangero J 《Nature genetics》2012,44(6):659-669
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. 相似文献
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Stolk L Perry JR Chasman DI He C Mangino M Sulem P Barbalic M Broer L Byrne EM Ernst F Esko T Franceschini N Gudbjartsson DF Hottenga JJ Kraft P McArdle PF Porcu E Shin SY Smith AV van Wingerden S Zhai G Zhuang WV Albrecht E Alizadeh BZ Aspelund T Bandinelli S Lauc LB Beckmann JS Boban M Boerwinkle E Broekmans FJ Burri A Campbell H Chanock SJ Chen C Cornelis MC Corre T Coviello AD d'Adamo P Davies G de Faire U de Geus EJ Deary IJ Dedoussis GV Deloukas P Ebrahim S Eiriksdottir G Emilsson V 《Nature genetics》2012,44(3):260-268
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. 相似文献
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RA Scott V Lagou RP Welch E Wheeler ME Montasser J Luan R Mägi RJ Strawbridge E Rehnberg S Gustafsson S Kanoni LJ Rasmussen-Torvik L Yengo C Lecoeur D Shungin S Sanna C Sidore PC Johnson JW Jukema T Johnson A Mahajan N Verweij G Thorleifsson JJ Hottenga S Shah AV Smith B Sennblad C Gieger P Salo M Perola NJ Timpson DM Evans BS Pourcain Y Wu JS Andrews J Hui LF Bielak W Zhao M Horikoshi P Navarro A Isaacs JR O'Connell K Stirrups V Vitart C Hayward T Esko E Mihailov RM Fraser T Fall BF Voight 《Nature genetics》2012,44(9):991-1005
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. 相似文献
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
Elks CE Perry JR Sulem P Chasman DI Franceschini N He C Lunetta KL Visser JA Byrne EM Cousminer DL Gudbjartsson DF Esko T Feenstra B Hottenga JJ Koller DL Kutalik Z Lin P Mangino M Marongiu M McArdle PF Smith AV Stolk L van Wingerden SH Zhao JH Albrecht E Corre T Ingelsson E Hayward C Magnusson PK Smith EN Ulivi S Warrington NM Zgaga L Alavere H Amin N Aspelund T Bandinelli S Barroso I Berenson GS Bergmann S Blackburn H Boerwinkle E Buring JE Busonero F Campbell H Chanock SJ Chen W Cornelis MC 《Nature genetics》2010,42(12):1077-1085
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???) and 9q31.2 (P = 2.2 × 10?33), we identified 30 new menarche loci (all P < 5 × 10??) and found suggestive evidence for a further 10 loci (P < 1.9 × 10??). 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. 相似文献
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Stein JL Medland SE Vasquez AA Hibar DP Senstad RE Winkler AM Toro R Appel K Bartecek R Bergmann Ø Bernard M Brown AA Cannon DM Chakravarty MM Christoforou A Domin M Grimm O Hollinshead M Holmes AJ Homuth G Hottenga JJ Langan C Lopez LM Hansell NK Hwang KS Kim S Laje G Lee PH Liu X Loth E Lourdusamy A Mattingsdal M Mohnke S Maniega SM Nho K Nugent AC O'Brien C Papmeyer M Pütz B Ramasamy A Rasmussen J Rijpkema M Risacher SL Roddey JC Rose EJ Ryten M Shen L Sprooten E Strengman E Teumer A 《Nature genetics》2012,44(5):552-561
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)). 相似文献
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Wain LV Verwoert GC O'Reilly PF Shi G Johnson T Johnson AD Bochud M Rice KM Henneman P Smith AV Ehret GB Amin N Larson MG Mooser V Hadley D Dörr M Bis JC Aspelund T Esko T Janssens AC Zhao JH Heath S Laan M Fu J Pistis G Luan J Arora P Lucas G Pirastu N Pichler I Jackson AU Webster RJ Zhang F Peden JF Schmidt H Tanaka T Campbell H Igl W Milaneschi Y Hottenga JJ Vitart V Chasman DI Trompet S Bragg-Gresham JL Alizadeh BZ Chambers JC Guo X Lehtimäki T Kühnel B Lopez LM Polašek O Boban M Nelson CP 《Nature genetics》2011,43(10):1005-1011
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP. 相似文献
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Gieger C Radhakrishnan A Cvejic A Tang W Porcu E Pistis G Serbanovic-Canic J Elling U Goodall AH Labrune Y Lopez LM Mägi R Meacham S Okada Y Pirastu N Sorice R Teumer A Voss K Zhang W Ramirez-Solis R Bis JC Ellinghaus D Gögele M Hottenga JJ Langenberg C Kovacs P O'Reilly PF Shin SY Esko T Hartiala J Kanoni S Murgia F Parsa A Stephens J van der Harst P Ellen van der Schoot C Allayee H Attwood A Balkau B Bastardot F Basu S Baumeister SE Biino G Bomba L Bonnefond A Cambien F Chambers JC Cucca F 《Nature》2011,480(7376):201-208
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. 相似文献
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Chambers JC Zhang W Sehmi J Li X Wass MN Van der Harst P Holm H Sanna S Kavousi M Baumeister SE Coin LJ Deng G Gieger C Heard-Costa NL Hottenga JJ Kühnel B Kumar V Lagou V Liang L Luan J Vidal PM Mateo Leach I O'Reilly PF Peden JF Rahmioglu N Soininen P Speliotes EK Yuan X Thorleifsson G Alizadeh BZ Atwood LD Borecki IB Brown MJ Charoen P Cucca F Das D de Geus EJ Dixon AL Döring A Ehret G Eyjolfsson GI Farrall M Forouhi NG Friedrich N Goessling W Gudbjartsson DF Harris TB Hartikainen AL Heath S 《Nature genetics》2011,43(11):1131-1138
Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. 相似文献
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