Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
Kanoni S., Graham SE., Wang Y., Surakka I., Ramdas S., Zhu X., Clarke SL., Bhatti KF., Vedantam S., Winkler TW., Locke AE., Marouli E., Zajac GJM., Wu K-HH., Ntalla I., Hui Q., Klarin D., Hilliard AT., Wang Z., Xue C., Thorleifsson G., Helgadottir A., Gudbjartsson DF., Holm H., Olafsson I., Hwang MY., Han S., Akiyama M., Sakaue S., Terao C., Kanai M., Zhou W., Brumpton BM., Rasheed H., Havulinna AS., Veturi Y., Pacheco JA., Rosenthal EA., Lingren T., Feng Q., Kullo IJ., Narita A., Takayama J., Martin HC., Hunt KA., Trivedi B., Haessler J., Giulianini F., Bradford Y., Miller JE., Campbell A., Lin K., Millwood IY., Rasheed A., Hindy G., Faul JD., Zhao W., Weir DR., Turman C., Huang H., Graff M., Choudhury A., Sengupta D., 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., Wood AR., Ji Y., Gao Z., Haworth S., Yousri NA., Mitchell RE., Chai JF., Aadahl M., Bjerregaard AA., Yao J., Manichaikul A., Hwu C-M., Hung Y-J., Warren HR., Ramirez J., Bork-Jensen J., Kårhus LL., Goel A., Sabater-Lleal M., Noordam R., Mauro P., Matteo F., McDaid AF., Marques-Vidal P., Wielscher M., Trompet S., Sattar N., Møllehave LT., Munz M., Zeng L., Huang J., Yang B., Poveda A., Kurbasic A., Lamina C., Forer L., Scholz M., Galesloot TE., Bradfield JP., Ruotsalainen SE., Daw E., Zmuda JM., Mitchell JS., Fuchsberger C., Christensen H., Brody JA., Vazquez-Moreno M., Feitosa MF., Wojczynski MK., Wang Z., Preuss MH., Mangino M., Christofidou P., Verweij N., Benjamins JW., Engmann J., Tsao NL., Verma A., Slieker RC., Lo KS., Zilhao NR., Le P., Kleber ME., Delgado GE., Huo S., Ikeda DD., Iha H., Yang J., Liu J., Demirkan A., Leonard HL., Marten J., Frank M., Schmidt B., 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., Nongmaithem SS., Bayyana S., Stringham HM., Irvin MR., Oldmeadow C., Kim H-N., Ryu S., Timmers PRHJ., Arbeeva L., Dorajoo R., Lange LA., 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., Chen S., Liu F., Yang J., Kentistou KA., Banas B., Nardone GG., Meidtner K., Bielak LF., Smith JA., Hebbar P., Farmaki A-E., Hofer E., Lin M., Concas MP., Vaccargiu S., van der Most PJ., Pitkänen N., Cade BE., van der Laan SW., Chitrala KN., Weiss S., Bentley AR., Doumatey AP., Adeyemo AA., Lee JY., Petersen ERB., Nielsen AA., 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., Hidalgo B., Giannakopoulou O., Cai Q., Obura MO., van Setten J., Li X., Liang J., Tang H., Terzikhan N., Shin JH., Jackson RD., Reiner AP., Martin LW., Chen Z., Li L., Kawaguchi T., Thiery J., Bis JC., 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., 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., Zimmermann ME., 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., Bandinelli S., Dedoussis G., Thanaraj TA., Kardia SLR., Peyser PA., Kato N., Schulze MB., Girotto G., Böger CA., Jung B., 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., Tusié-Luna T., Aguilar-Salinas CA., Adair LS., Bechayda SA., de Silva HJ., Wickremasinghe AR., Krauss RM., Wu J-Y., Zheng W., 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., Hunt SC., Walker M., Koistinen HA., Chandak GR., Mercader JM., Costanzo MC., Jang D., Burtt NP., Villalpando CG., Orozco L., Fornage M., Tai E., 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., Jin Z-B., Qu J., Hishigaki H., Lin X., März W., Gudnason V., Tardif J-C., Lettre G., Hart LMT., Elders PJM., Damrauer SM., Kumari M., Kivimaki M., van der Harst P., Spector TD., Loos RJF., Province MA., Parra EJ., Cruz M., Psaty BM., Brandslund I., Pramstaller PP., Rotimi CN., 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., Francesco C., Mook-Kanamori DO., van Dijk KW., Watkins H., Strachan DP., Grarup N., Sever P., Poulter N., Chuang L-M., Rotter JI., Dantoft TM., Karpe F., Neville MJ., Timpson NJ., Cheng C-Y., Wong T-Y., Khor CC., Li H., Sabanayagam C., Peters A., Gieger C., Hattersley AT., Pedersen NL., Magnusson PKE., Boomsma DI., Willemsen AHM., Cupples L., 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., Hazelhurst S., Ramsay M., North KE., Daviglus M., Kraft P., Martin NG., Whitfield JB., Abbas S., Saleheen D., Walters RG., Holmes MV., Black C., Smith BH., Baras A., Justice AE., Buring JE., Ridker PM., Chasman DI., Kooperberg C., Tamiya G., Yamamoto M., van Heel DA., Trembath RC., 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., Kim B-J., Thorsteinsdottir U., Stefansson K., Zhang J., Chen Y., Ho Y-L., Lynch JA., Rader DJ., Tsao PS., Chang K-M., Cho K., O'Donnell CJ., Gaziano JM., Wilson PWF., Frayling TM., Hirschhorn JN., Kathiresan S., Mohlke KL., Sun YV., Morris AP., Boehnke M., Brown CD., Natarajan P., Deloukas P., Willer CJ., Assimes TL., Peloso GM.
BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.