Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.
Christophersen IE., Rienstra M., Roselli C., Yin X., Geelhoed B., Barnard J., Lin H., Arking DE., Smith AV., Albert CM., Chaffin M., Tucker NR., Li M., Klarin D., Bihlmeyer NA., Low S-K., Weeke PE., Müller-Nurasyid M., Smith JG., Brody JA., Niemeijer MN., Dörr M., Trompet S., Huffman J., Gustafsson S., Schurmann C., Kleber ME., Lyytikäinen L-P., Seppälä I., Malik R., Horimoto ARVR., Perez M., Sinisalo J., Aeschbacher S., Thériault S., Yao J., Radmanesh F., Weiss S., Teumer A., Choi SH., Weng L-C., Clauss S., Deo R., Rader DJ., Shah SH., Sun A., Hopewell JC., Debette S., Chauhan G., Yang Q., Worrall BB., Paré G., Kamatani Y., Hagemeijer YP., Verweij N., Siland JE., Kubo M., Smith JD., Van Wagoner DR., Bis JC., Perz S., Psaty BM., Ridker PM., Magnani JW., Harris TB., Launer LJ., Shoemaker MB., Padmanabhan S., Haessler J., Bartz TM., Waldenberger M., Lichtner P., Arendt M., Krieger JE., Kähönen M., Risch L., Mansur AJ., Peters A., Smith BH., Lind L., Scott SA., Lu Y., Bottinger EB., Hernesniemi J., Lindgren CM., Wong JA., Huang J., Eskola M., Morris AP., Ford I., Reiner AP., Delgado G., Chen LY., Chen Y-DI., Sandhu RK., Li M., Boerwinkle E., Eisele L., Lannfelt L., Rost N., Anderson CD., Taylor KD., Campbell A., Magnusson PK., Porteous D., Hocking LJ., Vlachopoulou E., Pedersen NL., Nikus K., Orho-Melander M., Hamsten A., Heeringa J., Denny JC., Kriebel J., Darbar D., Newton-Cheh C., Shaffer C., Macfarlane PW., Heilmann-Heimbach S., Almgren P., Huang PL., Sotoodehnia N., Soliman EZ., Uitterlinden AG., Hofman A., Franco OH., Völker U., Jöckel K-H., Sinner MF., Lin HJ., Guo X., METASTROKE Consortium of the ISGC None., Neurology Working Group of the CHARGE Consortium None., Dichgans M., Ingelsson E., Kooperberg C., Melander O., Loos RJF., Laurikka J., Conen D., Rosand J., van der Harst P., Lokki M-L., Kathiresan S., Pereira A., Jukema JW., Hayward C., Rotter JI., März W., Lehtimäki T., Stricker BH., Chung MK., Felix SB., Gudnason V., Alonso A., Roden DM., Kääb S., Chasman DI., Heckbert SR., Benjamin EJ., Tanaka T., Lunetta KL., Lubitz SA., Ellinor PT., AFGen Consortium None.
Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.