The power of genetic diversity in genome-wide association studies of lipids.
Graham SE., Clarke SL., Wu K-HH., Kanoni S., Zajac GJM., Ramdas S., Surakka I., Ntalla I., Vedantam S., Winkler TW., Locke AE., Marouli E., Hwang MY., Han S., Narita A., Choudhury A., Bentley AR., Ekoru K., Verma A., Trivedi B., Martin HC., Hunt KA., Hui Q., Klarin D., Zhu X., Thorleifsson G., Helgadottir A., Gudbjartsson DF., Holm H., Olafsson I., Akiyama M., Sakaue S., Terao C., Kanai M., Zhou W., Brumpton BM., Rasheed H., Ruotsalainen SE., Havulinna AS., Veturi Y., Feng Q., Rosenthal EA., Lingren T., Pacheco JA., Pendergrass SA., Haessler J., Giulianini F., Bradford Y., Miller JE., Campbell A., Lin K., Millwood IY., Hindy G., Rasheed A., Faul JD., Zhao W., Weir DR., Turman C., Huang H., Graff M., Mahajan A., Brown MR., Zhang W., Yu K., Schmidt EM., Pandit A., Gustafsson S., Yin X., Luan J., Zhao J-H., Matsuda F., Jang H-M., Yoon K., Medina-Gomez C., Pitsillides A., Hottenga JJ., Willemsen G., Wood AR., Ji Y., Gao Z., Haworth S., Mitchell RE., Chai JF., Aadahl M., Yao J., Manichaikul A., Warren HR., Ramirez J., Bork-Jensen J., Kårhus LL., Goel A., Sabater-Lleal M., Noordam R., Sidore C., Fiorillo E., McDaid AF., Marques-Vidal P., Wielscher M., Trompet S., Sattar N., Møllehave LT., Thuesen BH., Munz M., Zeng L., Huang J., Yang B., Poveda A., Kurbasic A., Lamina C., Forer L., Scholz M., Galesloot TE., Bradfield JP., Daw EW., Zmuda JM., Mitchell JS., Fuchsberger C., Christensen H., Brody JA., Feitosa MF., Wojczynski MK., Preuss M., Mangino M., Christofidou P., Verweij N., Benjamins JW., Engmann J., Kember RL., Slieker RC., Lo KS., Zilhao NR., Le P., Kleber ME., Delgado GE., Huo S., Ikeda DD., Iha H., Yang J., Liu J., Leonard HL., Marten J., Schmidt B., Arendt M., Smyth LJ., Cañadas-Garre M., Wang C., Nakatochi M., Wong A., Hutri-Kähönen N., Sim X., Xia R., Huerta-Chagoya A., Fernandez-Lopez JC., Lyssenko V., Ahmed M., Jackson AU., Irvin MR., Oldmeadow C., Kim H-N., Ryu S., Timmers PRHJ., Arbeeva L., Dorajoo R., Lange LA., Chai X., Prasad G., Lorés-Motta L., Pauper M., Long J., Li X., Theusch E., Takeuchi F., Spracklen CN., Loukola A., Bollepalli S., Warner SC., Wang YX., Wei WB., Nutile T., Ruggiero D., Sung YJ., Hung Y-J., Chen S., Liu F., Yang J., Kentistou KA., Gorski M., Brumat M., Meidtner K., Bielak LF., Smith JA., Hebbar P., Farmaki A-E., Hofer E., Lin M., Xue C., Zhang J., Concas MP., Vaccargiu S., van der Most PJ., Pitkänen N., Cade BE., Lee J., van der Laan SW., Chitrala KN., Weiss S., Zimmermann ME., Lee JY., Choi HS., Nethander M., Freitag-Wolf S., Southam L., Rayner NW., Wang CA., Lin S-Y., Wang J-S., Couture C., Lyytikäinen L-P., Nikus K., Cuellar-Partida G., Vestergaard H., Hildalgo B., Giannakopoulou O., Cai Q., Obura MO., van Setten J., Li X., Schwander K., Terzikhan N., Shin JH., Jackson RD., Reiner AP., Martin LW., Chen Z., Li L., Highland HM., Young KL., Kawaguchi T., Thiery J., Bis JC., Nadkarni GN., Launer LJ., Li H., Nalls MA., Raitakari OT., Ichihara S., Wild SH., Nelson CP., Campbell H., Jäger S., Nabika T., Al-Mulla F., Niinikoski H., Braund PS., Kolcic I., Kovacs P., Giardoglou T., Katsuya T., Bhatti KF., de Kleijn D., de Borst GJ., Kim EK., Adams HHH., Ikram MA., Zhu X., Asselbergs FW., Kraaijeveld AO., Beulens JWJ., Shu X-O., Rallidis LS., Pedersen O., Hansen T., Mitchell P., Hewitt AW., Kähönen M., Pérusse L., Bouchard C., Tönjes A., Chen Y-DI., Pennell CE., Mori TA., Lieb W., Franke A., Ohlsson C., Mellström D., Cho YS., Lee H., Yuan J-M., Koh W-P., Rhee SY., Woo J-T., Heid IM., Stark KJ., Völzke H., Homuth G., Evans MK., Zonderman AB., Polasek O., Pasterkamp G., Hoefer IE., Redline S., Pahkala K., Oldehinkel AJ., Snieder H., Biino G., Schmidt R., Schmidt H., Chen YE., Bandinelli S., Dedoussis G., Thanaraj TA., Kardia SLR., Kato N., Schulze MB., Girotto G., Jung B., Böger CA., Joshi PK., Bennett DA., De Jager PL., Lu X., Mamakou V., Brown M., Caulfield MJ., Munroe PB., Guo X., Ciullo M., Jonas JB., Samani NJ., Kaprio J., Pajukanta P., Adair LS., Bechayda SA., de Silva HJ., Wickremasinghe AR., Krauss RM., Wu J-Y., Zheng W., den Hollander AI., Bharadwaj D., Correa A., Wilson JG., Lind L., Heng C-K., Nelson AE., Golightly YM., Wilson JF., Penninx B., Kim H-L., Attia J., Scott RJ., Rao DC., Arnett DK., Walker M., Koistinen HA., Chandak GR., Yajnik CS., Mercader JM., Tusié-Luna T., Aguilar-Salinas CA., Villalpando CG., Orozco L., Fornage M., Tai ES., van Dam RM., Lehtimäki T., Chaturvedi N., Yokota M., Liu J., Reilly DF., McKnight AJ., Kee F., Jöckel K-H., McCarthy MI., Palmer CNA., Vitart V., Hayward C., Simonsick E., van Duijn CM., Lu F., Qu J., Hishigaki H., Lin X., März W., Parra EJ., Cruz M., Gudnason V., Tardif J-C., Lettre G., 't Hart LM., Elders PJM., Damrauer SM., Kumari M., Kivimaki M., van der Harst P., Spector TD., Loos RJF., Province MA., Psaty BM., Brandslund I., Pramstaller PP., Christensen K., Ripatti S., Widén E., Hakonarson H., Grant SFA., Kiemeney LALM., de Graaf J., Loeffler M., Kronenberg F., Gu D., Erdmann J., Schunkert H., Franks PW., Linneberg A., Jukema JW., Khera AV., Männikkö M., Jarvelin M-R., Kutalik Z., Cucca F., Mook-Kanamori DO., van Dijk KW., Watkins H., Strachan DP., Grarup N., Sever P., Poulter N., Rotter JI., Dantoft TM., Karpe F., Neville MJ., Timpson NJ., Cheng C-Y., Wong T-Y., Khor CC., Sabanayagam C., Peters A., Gieger C., Hattersley AT., Pedersen NL., Magnusson PKE., Boomsma DI., de Geus EJC., Cupples LA., van Meurs JBJ., Ghanbari M., Gordon-Larsen P., Huang W., Kim YJ., Tabara Y., Wareham NJ., Langenberg C., Zeggini E., Kuusisto J., Laakso M., Ingelsson E., Abecasis G., Chambers JC., Kooner JS., de Vries PS., Morrison AC., North KE., Daviglus M., Kraft P., Martin NG., Whitfield JB., Abbas S., Saleheen D., Walters RG., Holmes MV., Black C., Smith BH., Justice AE., Baras A., Buring JE., Ridker PM., Chasman DI., Kooperberg C., Wei W-Q., Jarvik GP., Namjou B., Hayes MG., Ritchie MD., Jousilahti P., Salomaa V., Hveem K., Åsvold BO., Kubo M., Kamatani Y., Okada Y., Murakami Y., Thorsteinsdottir U., Stefansson K., Ho Y-L., Lynch JA., Rader DJ., Tsao PS., Chang K-M., Cho K., O'Donnell CJ., Gaziano JM., Wilson P., Rotimi CN., Hazelhurst S., Ramsay M., Trembath RC., van Heel DA., Tamiya G., Yamamoto M., Kim B-J., Mohlke KL., Frayling TM., Hirschhorn JN., Kathiresan S., VA Million Veteran Program None., Global Lipids Genetics Consortium* None., Boehnke M., Natarajan P., Peloso GM., Brown CD., Morris AP., Assimes TL., Deloukas P., Sun YV., Willer CJ.
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.