A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans
Timpson NJ., Walter K., Min JL., Tachmazidou I., Malerba G., Shin S-Y., Chen L., Futema M., Southam L., Iotchkova V., Cocca M., Huang J., Memari Y., McCarthy S., Danecek P., Muddyman D., Mangino M., Menni C., Perry JRB., Ring SM., Gaye A., Dedoussis G., Farmaki A-E., Burton P., Talmud PJ., Gambaro G., Spector TD., Smith GD., Durbin R., Richards JB., Humphries SE., Zeggini E., Soranzo N., Al Turki S., Anderson C., Anney R., Antony D., Soler Artigas M., Ayub M., Balasubramaniam S., Barrett JC., Barroso I., Beales P., Bentham J., Bhattacharya S., Birney E., Blackwood D., Bobrow M., Bochukova E., Bolton P., Bounds R., Boustred C., Breen G., Calissano M., Carss K., Chatterjee K., Chen L., Ciampi A., Cirak S., Clapham P., Clement G., Coates G., Collier D., Cosgrove C., Cox T., Craddock N., Crooks L., Curran S., Curtis D., Daly A., Danecek P., Davey Smith G., Day-Williams A., Day INM., Down T., Du Y., Dunham I., Durbin R., Edkins S., Ellis P., Evans D., Faroogi S., Fatemifar G., Fitzpatrick DR., Flicek P., Flyod J., Foley AR., Franklin CS., Futema M., Gallagher L., Gaunt T., Geihs M., Geschwind D., Greenwood C., Griffin H., Grozeva D., Guo X., Guo X., Gurling H., Hart D., Hendricks A., Holmans P., Howie B., Huang J., Huang L., Hubbard T., Humphries SE., Hurles ME., Hysi P., Jackson DK., Jamshidi Y., Jing T., Joyce C., Kaye J., Keane T., Keogh J., Kemp J., Kennedy K., Kolb-Kokocinski A., Lachance G., Langford C., Lawson D., Lee I., Lek M., Liang J., Lin H., Li R., Li Y., Liu R., Lönnqvist J., Lopes M., Lotchkova V., MacArthur D., Marchini J., Maslen J., Massimo M., Mathieson I., Marenne G., McCarthy S., McGuffin P., McIntosh A., McKechanie AG., McQuillin A., Memari Y., Metrustry S., Min J., Mitchison H., Moayyeri A., Morris J., Muddyman D., Muntoni F., Northstone K., O'Donnovan M., Onoufriadis A., O'Rahilly S., Oualkacha K., Owen MJ., Palotie A., Panoutsopoulou K., Parker V., Parr JR., Paternoster L., Paunio T., Payne F., Perry J., Pietilainen O., Plagnol V., Quaye L., Quail MA., Raymond L., Rehnström K., Richards B., Ring S., Ritchie GRS., Roberts N., Savage DB., Scambler P., Schiffels S., Schmidts M., Schoenmakers N., Semple RK., Serra E., Sharp SI., Shihab H., Shin S-Y., Skuse D., Small K., Soranzo N., Southam L., Spasic-Boskovic O., Spector T., St Clair D., Stalker J., Stevens E., St Pourcian B., Sun J., Surdulescu G., Suvisaari J., Tachmazidou I., Timpson N., Tobin MD., Valdes A., Van Kogelenberg M., Vijayarangakannan P., Visscher PM., Wain LV., Walter K., Walters JTR., Wang G., Wang J., Wang Y., Ward K., Wheeler E., Whyte T., Williams H., Williamson KA., Wilson C., Wilson SG., Wong K., Xu C., Yang J., Zeggini E., Zhang F., Zhang P., Zheng H-F.
AbstractThe analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.