Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE study
Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of 6 correlated (Pearson's r range: |0.04-0.92|) RBC traits in up to 19 036 African Americans and 19 562 Hispanic/Latino participants of the Population Architecture using Genomics and Epidemiology consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11 000 SNPs flanking 13 previously identified association signals as well as 150 000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p < 1.7 × 10−4); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p = 1.9 × 10−7). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations.
|Persistent URL||dx.doi.org/10.1002/ajh.25161, hdl.handle.net/1765/109872|
|Journal||American Journal of Hematology|
Hodonsky, C.J. (Chani J.), Schurmann, C, Schick, U.M, Kocarnik, J. (Jonathan), Tao, S, van Rooij, F.J.A, … Avery, C.L. (2018). Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE study. American Journal of Hematology, 93(8), 1061–1073. doi:10.1002/ajh.25161