A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.
Ramdas S., Judd J., Graham SE., Kanoni S., Wang Y., Surakka I., Wenz B., Clarke SL., Chesi A., Wells A., 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., Mitchell RE., Chai JF., Aadahl M., Bjerregaard AA., Yao J., Manichaikul A., Lee W-J., Hsiung CA., 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., Schönherr S., Forer L., Scholz M., Galesloot TE., Bradfield JP., Ruotsalainen SE., Daw EW., Zmuda JM., Mitchell JS., Fuchsberger C., Christensen H., Brody JA., Le P., Feitosa MF., Wojczynski MK., Hemerich D., Preuss M., Mangino M., Christofidou P., Verweij N., Benjamins JW., Engmann J., Noah TL., Verma A., Slieker RC., Lo KS., Zilhao NR., Kleber ME., Delgado GE., Huo S., Ikeda DD., Iha H., Yang J., Liu J., Demirkan A., Leonard HL., Marten J., Emmel C., 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., Sankareswaran A., 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., Morgan A., 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., He KY., 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., Ida Chen Y-D., 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., 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., 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., Scott LJ., Koistinen HA., Chandak GR., Mercader JM., 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., Jin Z-B., Lu F., Hishigaki H., Lin X., März W., Gudnason V., Tardif J-C., Lettre G., T Hart LM., Elders PJM., Rader DJ., 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 L., 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., Willems van Dijk K., Watkins H., Strachan DP., Grarup N., Sever P., Poulter N., Huey-Herng Sheu W., 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., de Geus EJC., Cupples LA., van Meurs JBJ., Ikram A., Ghanbari M., Gordon-Larsen P., Huang W., Kim YJ., Tabara Y., Wareham NJ., Langenberg C., Zeggini E., Tuomilehto J., 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 YE., Ho Y-L., Lynch JA., Tsao PS., Chang K-M., Cho K., O'Donnell CJ., Gaziano JM., Wilson P., Mohlke KL., Frayling TM., Hirschhorn JN., Kathiresan S., Boehnke M., Million Veterans Program None., Global Lipids Genetics Consortium None., Struan Grant None., Natarajan P., Sun YV., Morris AP., Deloukas P., Peloso G., Assimes TL., Willer CJ., Zhu X., Brown CD.
A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.