Genetic diversity fuels gene discovery for tobacco and alcohol use
Saunders GRB., Wang X., Chen F., Jang SK., Liu M., Wang C., Gao S., Jiang Y., Khunsriraksakul C., Otto JM., Addison C., Akiyama M., Albert CM., Aliev F., Alonso A., Arnett DK., Ashley-Koch AE., Ashrani AA., Barnes KC., Barr RG., Bartz TM., Becker DM., Bielak LF., Benjamin EJ., Bis JC., Bjornsdottir G., Blangero J., Bleecker ER., Boardman JD., Boerwinkle E., Boomsma DI., Boorgula MP., Bowden DW., Brody JA., Cade BE., Chasman DI., Chavan S., Chen YDI., Chen Z., Cheng I., Cho MH., Choquet H., Cole JW., Cornelis MC., Cucca F., Curran JE., de Andrade M., Dick DM., Docherty AR., Duggirala R., Eaton CB., Ehringer MA., Esko T., Faul JD., Silva LF., Fiorillo E., Fornage M., Freedman BI., Gabrielsen ME., Garrett ME., Gharib SA., Gieger C., Gillespie N., Glahn DC., Gordon SD., Gu CC., Gu D., Gudbjartsson DF., Guo X., Haessler J., Hall ME., Haller T., Harris KM., He J., Herd P., Hewitt JK., Hickie I., Hidalgo B., Hokanson JE., Hopfer C., Hottenga JJ., Hou L., Huang H., Hung YJ., Hunter DJ., Hveem K., Hwang SJ., Hwu CM., Iacono W., Irvin MR., Jee YH., Johnson EO., Joo YY., Jorgenson E., Justice AE., Kamatani Y., Kaplan RC., Kaprio J., Kardia SLR., Keller MC.
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.