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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

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???) 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.

SUBMITTER: Elks CE

PROVIDER: S-EPMC3140055 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

Elks Cathy E CE Perry John R B JR Sulem Patrick P Chasman Daniel I DI Franceschini Nora N He Chunyan C Lunetta Kathryn L KL Visser Jenny A JA Byrne Enda M EM Cousminer Diana L DL Gudbjartsson Daniel F DF Esko Tõnu T Feenstra Bjarke B Hottenga Jouke-Jan JJ Koller Daniel L DL Kutalik Zoltán Z Lin Peng P Mangino Massimo M Marongiu Mara M McArdle Patrick F PF Smith Albert V AV Stolk Lisette L van Wingerden Sophie H SH Zhao Jing Hua JH Albrecht Eva E Corre Tanguy T Ingelsson Erik E Hayward Caroline C Magnusson Patrik K E PK Smith Erin N EN Ulivi Shelia S Warrington Nicole M NM Zgaga Lina L Alavere Helen H Amin Najaf N Aspelund Thor T Bandinelli Stefania S Barroso Inês I Berenson Gerald S GS Bergmann Sven S Blackburn Hannah H Boerwinkle Eric E Buring Julie E JE Busonero Fabio F Campbell Harry H Chanock Stephen J SJ Chen Wei W Cornelis Marilyn C MC Couper David D Coviello Andrea D AD d'Adamo Pio P de Faire Ulf U de Geus Eco J C EJ Deloukas Panos P Döring Angela A Smith George Davey GD Easton Douglas F DF Eiriksdottir Gudny G Emilsson Valur V Eriksson Johan J Ferrucci Luigi L Folsom Aaron R AR Foroud Tatiana T Garcia Melissa M Gasparini Paolo P Geller Frank F Gieger Christian C Gudnason Vilmundur V Hall Per P Hankinson Susan E SE Ferreli Liana L Heath Andrew C AC Hernandez Dena G DG Hofman Albert A Hu Frank B FB Illig Thomas T Järvelin Marjo-Riitta MR Johnson Andrew D AD Karasik David D Khaw Kay-Tee KT Kiel Douglas P DP Kilpeläinen Tuomas O TO Kolcic Ivana I Kraft Peter P Launer Lenore J LJ Laven Joop S E JS Li Shengxu S Liu Jianjun J Levy Daniel D Martin Nicholas G NG McArdle Wendy L WL Melbye Mads M Mooser Vincent V Murray Jeffrey C JC Murray Sarah S SS Nalls Michael A MA Navarro Pau P Nelis Mari M Ness Andrew R AR Northstone Kate K Oostra Ben A BA Peacock Munro M Palmer Lyle J LJ Palotie Aarno A Paré Guillaume G Parker Alex N AN Pedersen Nancy L NL Peltonen Leena L Pennell Craig E CE Pharoah Paul P Polasek Ozren O Plump Andrew S AS Pouta Anneli A Porcu Eleonora E Rafnar Thorunn T Rice John P JP Ring Susan M SM Rivadeneira Fernando F Rudan Igor I Sala Cinzia C Salomaa Veikko V Sanna Serena S Schlessinger David D Schork Nicholas J NJ Scuteri Angelo A Segrè Ayellet V AV Shuldiner Alan R AR Soranzo Nicole N Sovio Ulla U Srinivasan Sathanur R SR Strachan David P DP Tammesoo Mar-Liis ML Tikkanen Emmi E Toniolo Daniela D Tsui Kim K Tryggvadottir Laufey L Tyrer Jonathon J Uda Manuela M van Dam Rob M RM van Meurs Joyce B J JB Vollenweider Peter P Waeber Gerard G Wareham Nicholas J NJ Waterworth Dawn M DM Weedon Michael N MN Wichmann H Erich HE Willemsen Gonneke G Wilson James F JF Wright Alan F AF Young Lauren L Zhai Guangju G Zhuang Wei Vivian WV Bierut Laura J LJ Boomsma Dorret I DI Boyd Heather A HA Crisponi Laura L Demerath Ellen W EW van Duijn Cornelia M CM Econs Michael J MJ Harris Tamara B TB Hunter David J DJ Loos Ruth J F RJ Metspalu Andres A Montgomery Grant W GW Ridker Paul M PM Spector Tim D TD Streeten Elizabeth A EA Stefansson Kari K Thorsteinsdottir Unnur U Uitterlinden André G AG Widen Elisabeth E Murabito Joanne M JM Ong Ken K KK Murray Anna A

Nature genetics 20101201 12

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 T ...[more]

PMID: 21102462

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Project description:Background & aimsA genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.MethodsWe obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.ResultsWe observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.ConclusionsIn this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

Publications

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

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