Adeyemo, A. | Search bioRxiv

bioRxiv2021

Polygenic Prediction of Type 2 Diabetes in Continental Africa

ObjectivePolygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa, and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. Research Design and MethodsUsing the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls). ResultsThe African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10th decile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10-6) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. ConclusionsAfrican American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.

genetics↗

bioRxiv2020

GWAS in Africans identifies novel lipids loci and demonstrates heterogenous association within Africa

BackgroundSerum lipids are biomarkers of cardiometabolic disease risk, and understanding the genomic factors contributing to their distribution has been of considerable interest. Large genome-wide association studies (GWAS) have identified over 150 lipids loci; however, GWAS of Africans (AF) are rare. Given the genomic diversity among those of African ancestry, it is expected that a GWAS in Africans could identify novel lipids loci. While GWAS have been conducted in African Americans (AA), such studies are not proxies for studies in continental Africans due to the drastically different environmental context. Therefore, we conducted a GWAS of 4,317 Africans enrolled in the Africa America Diabetes Mellitus study. Methods and ResultsWe used linear mixed models of the inverse normal transformations of covariate-djusted residuals of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG), and TG/HDLC, with adjustment for three principal components and the random effect of relatedness. Replication of loci associated at p<5x10-8 was attempted in 9,542 AA. Meta-analysis of AF and AA was also conducted. We also conducted analyses that excluded the relatively small number of East Africans. We evaluated known lipids loci in Africans using both exact replication and "local" replication, which accounts for interethnic differences in linkage disequilibrium. In our main analysis, we identified 23 novel associations in Africans. Of the 14 of these that were able to be tested in AA, two associations replicated (GPNMB-TG and ENPP1-TG). Two additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG and TLL2-CHOL). Analyses considering only those with predominantly West African ancestry (Nigeria, Ghana, and AA) yielded new insights: ORC5-LDLC and chr20:60973327-CHOL. ConclusionsWhile functional work will be useful to confirm and understand the biological mechanisms underlying these associations, this study demonstrates the utility of conducting large-scale genomic analyses in Africans for discovering novel loci. The functional significance of some of these loci in relation to lipids remains to be elucidated, yet some have known connections to lipids pathways. For instance, rs147706369 (intronic, TLL2) alters a regulatory motif for sterol regulatory element-binding proteins (SREBPs), which are a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid, and triglyceride synthesis.

genomics↗