Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.
Kilpeläinen TO., Bentley AR., Noordam R., Sung YJ., Schwander K., Winkler TW., Jakupović H., Chasman DI., Manning A., Ntalla I., Aschard H., Brown MR., de Las Fuentes L., Franceschini N., Guo X., Vojinovic D., Aslibekyan S., Feitosa MF., Kho M., Musani SK., Richard M., Wang H., Wang Z., Bartz TM., Bielak LF., Campbell A., Dorajoo R., Fisher V., Hartwig FP., Horimoto ARVR., Li C., Lohman KK., Marten J., Sim X., Smith AV., Tajuddin SM., Alver M., Amini M., Boissel M., Chai JF., Chen X., Divers J., Evangelou E., Gao C., Graff M., Harris SE., He M., Hsu F-C., Jackson AU., Zhao JH., Kraja AT., Kühnel B., Laguzzi F., Lyytikäinen L-P., Nolte IM., Rauramaa R., Riaz M., Robino A., Rueedi R., Stringham HM., Takeuchi F., van der Most PJ., Varga TV., Verweij N., Ware EB., Wen W., Li X., Yanek LR., Amin N., Arnett DK., Boerwinkle E., Brumat M., Cade B., Canouil M., Chen Y-DI., Concas MP., Connell J., de Mutsert R., de Silva HJ., de Vries PS., Demirkan A., Ding J., Eaton CB., Faul JD., Friedlander Y., Gabriel KP., Ghanbari M., Giulianini F., Gu CC., Gu D., Harris TB., He J., Heikkinen S., Heng C-K., Hunt SC., Ikram MA., Jonas JB., Koh W-P., Komulainen P., Krieger JE., Kritchevsky SB., Kutalik Z., Kuusisto J., Langefeld CD., Langenberg C., Launer LJ., Leander K., Lemaitre RN., Lewis CE., Liang J., Lifelines Cohort Study None., Liu J., Mägi R., Manichaikul A., Meitinger T., Metspalu A., Milaneschi Y., Mohlke KL., Mosley TH., Murray AD., Nalls MA., Nang E-EK., Nelson CP., Nona S., Norris JM., Nwuba CV., O'Connell J., Palmer ND., Papanicolau GJ., Pazoki R., Pedersen NL., Peters A., Peyser PA., Polasek O., Porteous DJ., Poveda A., Raitakari OT., Rich SS., Risch N., Robinson JG., Rose LM., Rudan I., Schreiner PJ., Scott RA., Sidney SS., Sims M., Smith JA., Snieder H., Sofer T., Starr JM., Sternfeld B., Strauch K., Tang H., Taylor KD., Tsai MY., Tuomilehto J., Uitterlinden AG., van der Ende MY., van Heemst D., Voortman T., Waldenberger M., Wennberg P., Wilson G., Xiang Y-B., Yao J., Yu C., Yuan J-M., Zhao W., Zonderman AB., Becker DM., Boehnke M., Bowden DW., de Faire U., Deary IJ., Elliott P., Esko T., Freedman BI., Froguel P., Gasparini P., Gieger C., Kato N., Laakso M., Lakka TA., Lehtimäki T., Magnusson PKE., Oldehinkel AJ., Penninx BWJH., Samani NJ., Shu X-O., van der Harst P., Van Vliet-Ostaptchouk JV., Vollenweider P., Wagenknecht LE., Wang YX., Wareham NJ., Weir DR., Wu T., Zheng W., Zhu X., Evans MK., Franks PW., Gudnason V., Hayward C., Horta BL., Kelly TN., Liu Y., North KE., Pereira AC., Ridker PM., Tai ES., van Dam RM., Fox ER., Kardia SLR., Liu C-T., Mook-Kanamori DO., Province MA., Redline S., van Duijn CM., Rotter JI., Kooperberg CB., Gauderman WJ., Psaty BM., Rice K., Munroe PB., Fornage M., Cupples LA., Rotimi CN., Morrison AC., Rao DC., Loos RJF.
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.