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Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

SUBMITTER: Lanktree MB

PROVIDER: S-EPMC3014369 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Lanktree Matthew B MB Guo Yiran Y Murtaza Muhammed M Glessner Joseph T JT Bailey Swneke D SD Onland-Moret N Charlotte NC Lettre Guillaume G Ongen Halit H Rajagopalan Ramakrishnan R Johnson Toby T Shen Haiqing H Nelson Christopher P CP Klopp Norman N Baumert Jens J Padmanabhan Sandosh S Pankratz Nathan N Pankow James S JS Shah Sonia S Taylor Kira K Barnard John J Peters Bas J BJ Maloney Cliona M CM Lobmeyer Maximilian T MT Stanton Alice A Zafarmand M Hadi MH Romaine Simon P R SP Mehta Amar A van Iperen Erik P A EP Gong Yan Y Price Tom S TS Smith Erin N EN Kim Cecilia E CE Li Yun R YR Asselbergs Folkert W FW Atwood Larry D LD Bailey Kristian M KM Bhatt Deepak D Bauer Florianne F Behr Elijah R ER Bhangale Tushar T Boer Jolanda M A JM Boehm Bernhard O BO Bradfield Jonathan P JP Brown Morris M Braund Peter S PS Burton Paul R PR Carty Cara C Chandrupatla Hareesh R HR Chen Wei W Connell John J Dalgeorgou Chrysoula C Boer Anthonius de Ad Drenos Fotios F Elbers Clara C CC Fang James C JC Fox Caroline S CS Frackelton Edward C EC Fuchs Barry B Furlong Clement E CE Gibson Quince Q Gieger Christian C Goel Anuj A Grobbee Diederik E DE Hastie Claire C Howard Philip J PJ Huang Guan-Hua GH Johnson W Craig WC Li Qing Q Kleber Marcus E ME Klein Barbara E K BE Klein Ronald R Kooperberg Charles C Ky Bonnie B Lacroix Andrea A Lanken Paul P Lathrop Mark M Li Mingyao M Marshall Vanessa V Melander Olle O Mentch Frank D FD Meyer Nuala J NJ Monda Keri L KL Montpetit Alexandre A Murugesan Gurunathan G Nakayama Karen K Nondahl Dave D Onipinla Abiodun A Rafelt Suzanne S Newhouse Stephen J SJ Otieno F George FG Patel Sanjey R SR Putt Mary E ME Rodriguez Santiago S Safa Radwan N RN Sawyer Douglas B DB Schreiner Pamela J PJ Simpson Claire C Sivapalaratnam Suthesh S Srinivasan Sathanur R SR Suver Christine C Swergold Gary G Sweitzer Nancy K NK Thomas Kelly A KA Thorand Barbara B Timpson Nicholas J NJ Tischfield Sam S Tobin Martin M Tomaszewski Maciej M Verschuren W M Monique WM Wallace Chris C Winkelmann Bernhard B Zhang Haitao H Zheng Dongling D Zhang Li L Zmuda Joseph M JM Clarke Robert R Balmforth Anthony J AJ Danesh John J Day Ian N IN Schork Nicholas J NJ de Bakker Paul I W PI Delles Christian C Duggan David D Hingorani Aroon D AD Hirschhorn Joel N JN Hofker Marten H MH Humphries Steve E SE Kivimaki Mika M Lawlor Debbie A DA Kottke-Marchant Kandice K Mega Jessica L JL Mitchell Braxton D BD Morrow David A DA Palmen Jutta J Redline Susan S Shields Denis C DC Shuldiner Alan R AR Sleiman Patrick M PM Smith George Davey GD Farrall Martin M Jamshidi Yalda Y Christiani David C DC Casas Juan P JP Hall Alistair S AS Doevendans Pieter A PA Christie Jason D JD Berenson Gerald S GS Murray Sarah S SS Illig Thomas T Dorn Gerald W GW Cappola Thomas P TP Boerwinkle Eric E Sever Peter P Rader Daniel J DJ Reilly Muredach P MP Caulfield Mark M Talmud Philippa J PJ Topol Eric E Engert James C JC Wang Kai K Dominiczak Anna A Hamsten Anders A Curtis Sean P SP Silverstein Roy L RL Lange Leslie A LA Sabatine Marc S MS Trip Mieke M Saleheen Danish D Peden John F JF Cruickshanks Karen J KJ März Winfried W O'Connell Jeffrey R JR Klungel Olaf H OH Wijmenga Cisca C Maitland-van der Zee Anke Hilse AH Schadt Eric E EE Johnson Julie A JA Jarvik Gail P GP Papanicolaou George J GJ Grant Struan F A SF Munroe Patricia B PB North Kari E KE Samani Nilesh J NJ Koenig Wolfgang W Gaunt Tom R TR Anand Sonia S SS van der Schouw Yvonne T YT Soranzo Nicole N Fitzgerald Garret A GA Reiner Alex A Hegele Robert A RA Hakonarson Hakon H Keating Brendan J BJ

American journal of human genetics 20101230 1

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), wit ...[more]

PMID: 21194676

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Project description:BACKGROUND:Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. OBJECTIVE:The objective of the study was to identify common genetic variants that are associated with macronutrient intake. DESIGN:We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. RESULTS:A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (? ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (? ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (? ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, ? ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)). CONCLUSION:Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Dataset Information

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Publications

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

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