Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.
Lanktree MB., Guo Y., Murtaza M., Glessner JT., Bailey SD., Onland-Moret NC., Lettre G., Ongen H., Rajagopalan R., Johnson T., Shen H., Nelson CP., Klopp N., Baumert J., Padmanabhan S., Pankratz N., Pankow JS., Shah S., Taylor K., Barnard J., Peters BJ., Maloney CM., Lobmeyer MT., Stanton A., Zafarmand MH., Romaine SPR., Mehta A., van Iperen EPA., Gong Y., Price TS., Smith EN., Kim CE., Li YR., Asselbergs FW., Atwood LD., Bailey KM., Bhatt D., Bauer F., Behr ER., Bhangale T., Boer JMA., Boehm BO., Bradfield JP., Brown M., Braund PS., Burton PR., Carty C., Chandrupatla HR., Chen W., Connell J., Dalgeorgou C., Boer AD., Drenos F., Elbers CC., Fang JC., Fox CS., Frackelton EC., Fuchs B., Furlong CE., Gibson Q., Gieger C., Goel A., Grobbee DE., Hastie C., Howard PJ., Huang G-H., Johnson WC., Li Q., Kleber ME., Klein BEK., Klein R., Kooperberg C., Ky B., Lacroix A., Lanken P., Lathrop M., Li M., Marshall V., Melander O., Mentch FD., Meyer NJ., Monda KL., Montpetit A., Murugesan G., Nakayama K., Nondahl D., Onipinla A., Rafelt S., Newhouse SJ., Otieno FG., Patel SR., Putt ME., Rodriguez S., Safa RN., Sawyer DB., Schreiner PJ., Simpson C., Sivapalaratnam S., Srinivasan SR., Suver C., Swergold G., Sweitzer NK., Thomas KA., Thorand B., Timpson NJ., Tischfield S., Tobin M., Tomaszewski M., Verschuren WMM., Wallace C., Winkelmann B., Zhang H., Zheng D., Zhang L., Zmuda JM., Clarke R., Balmforth AJ., Danesh J., Day IN., Schork NJ., de Bakker PIW., Delles C., Duggan D., Hingorani AD., Hirschhorn JN., Hofker MH., Humphries SE., Kivimaki M., Lawlor DA., Kottke-Marchant K., Mega JL., Mitchell BD., Morrow DA., Palmen J., Redline S., Shields DC., Shuldiner AR., Sleiman PM., Smith GD., Farrall M., Jamshidi Y., Christiani DC., Casas JP., Hall AS., Doevendans PA., Christie JD., Berenson GS., Murray SS., Illig T., Dorn GW., Cappola TP., Boerwinkle E., Sever P., Rader DJ., Reilly MP., Caulfield M., Talmud PJ., Topol E., Engert JC., Wang K., Dominiczak A., Hamsten A., Curtis SP., Silverstein RL., Lange LA., Sabatine MS., Trip M., Saleheen D., Peden JF., Cruickshanks KJ., März W., O'Connell JR., Klungel OH., Wijmenga C., Maitland-van der Zee AH., Schadt EE., Johnson JA., Jarvik GP., Papanicolaou GJ., Hugh Watkins on behalf of PROCARDIS None., Grant SFA., Munroe PB., North KE., Samani NJ., Koenig W., Gaunt TR., Anand SS., van der Schouw YT., Meena Kumari on behalf of the Whitehall II Study and the WHII 50K Group None., Soranzo N., Fitzgerald GA., Reiner A., Hegele RA., Hakonarson H., Keating BJ.
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.