- Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) study.
- We confirmed multiple previously reported genome- wide significant variants in the single variant association analysis and multiple genes using PrediXcan.
- The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
- If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..
- Correspondence:
[email protected].
- The Population Architecture using Genomics and Epi- demiology (PAGE) Study funded by the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities was initiated to systematically characterize the genetic architecture underlying complex diseases and related quantitative traits among underrepresented minority populations in the U.S.
- In the absence of evidence of genomic inflation in ancestry-specific and ancestry-combined meta-analysis (ranged: 0.936 to 1.150, Supplemental Table 2), the num- ber of loci that reached genome-wide significance ([P <.
- The largest numbers of significant find- ings for WBC and NEU were from AA-specific analysis, most of which showed significant associations only in the AA (Supplemental Table 3).
- Top variants at significant loci in the ancestry-combined and ancestry-specific ana- lysis are presented in Supplemental Table 3..
- In the discovery stage, we identified two novel loci that reached suggestive significance (INSIG1 and IGF1, P <.
- WBC white blood cell count.
- The six novel findings we identified in the single-trait associ- ation analysis also showed suggestive evidence of associ- ation in the multi-trait analysis (P≤9.85E-7, Supplemental Table 4)..
- In the replication stage, the two novel loci and the four novel associations at established loci were examined in independent populations from the Blood Cell Consor- tium (BCX) [23] after excluding the overlapped BioMe multi-ethnic and WHI EA samples.
- None of the six loci showed evidence of association in the rep- lication stage (Supplemental Table 5).
- A literature review that included genetic variants indexed in the GWAS Catalog (latest access date: Sep- tember 23, 2020) or targeted chips (Metabochip or Exo- mechip identified a total of 8531 unique variants mapping to 1158 known white blood cell and platelet loci (based on 2 Mb genomic regions).
- Of the 16 comparisons (eight traits and two ancestral Table 2 Novel findings identified in the ancestry-specific and ancestry-combined meta-analyses a.
- WBC white blood cell.
- We examined the six novel findings and their LD proxies in the gchromVAR results using the UK BioBank (UKBB) and BCX data, which quanti- fied the enrichment of the 95% credible set variants from the trans-ethnic and ethnic-specific results within re- gions of accessible chromatin identified by ATAC-seq in 18 hematopoietic populations [34, 35].
- Annotation of the independent variants we identified in the stepwise conditional analysis was performed by extracting information of each available variant from the whole genome sequence annotator (WGSA) dataset (Supplemental Table 12).
- We also examined these independent variants in the BCX gchromVAR results.
- Evidence from gene expression data in the Consortium for the Archi- tecture of Gene Expression (CAGE), the Depression Genes and Networks (DGN), the eQTLGen Consortium, and the Netherlands Study of Depression and Anxiety/.
- The failure to replicate our novel findings in the BCX Con- sortium may have, at least in part, resulted from the relatively modest sample sizes of AA and HL samples in BCX (roughly 13,000 AA and 6500 HL participants after excluding overlapping BioMe multi-ethnic samples), as most of our novel findings are more common in AA and HL populations.
- Among the six novel findings we identified in the ancestry-combined meta- analysis, half of them were mainly driven by association signals in AA and HL populations.
- Among the six loci showing evidence of independent signals in the stepwise condi- tional analysis, two of them harbored variants whose as- sociations were mainly driven by AA and/or HL populations.
- More significant loci were identified in the ancestry- combined analysis except for WBC and NEU, where most significant results were in AA, suggesting improved power when combining all samples and the potential to uncover loci driven by all ancestral groups..
- First, the sample sizes of the underrepresented AA and HL populations remained limited compared to sample sizes available in Euro- centric GWAS (with over 500,000 EA participants in the BCX Consortium [23.
- The relatively modest sample sizes limited the power to identify additional novel loci in the univariate association analyses and the multi-trait association analysis.
- to the absence of novel gene findings in the PrediXcan analysis, reinforcing the need to collect transcriptomics data and construct tailored models in minority populations..
- In conclusion, the ancestrally diverse populations in the PAGE Study facilitated the discovery of both ancestry-specific and ancestry-agnostic findings at puta- tive novel loci and previously established regions for as- sociation with white blood cell and platelet traits..
- We identified six potential novel findings for five of the eight examined white blood cell and platelet traits in the ancestrally diverse populations from PAGE.
- In the discovery stage, our analysis included up to 64, 784 participants of self-identified AA (n=16,201), HL (n=21,347), or EA (n=27,236) race/ethnicity from four cohort studies and one biobank (Table 1): the Athero- sclerosis Risk in Communities Study (ARIC), the Coron- ary Artery Risk Development in Young Adults Study (CARDIA), the Hispanic Community Health Study/.
- We studied eight hematological traits as defined in the standard clinical complete blood count (CBC) analysis, measuring properties of white blood cells (WBC, BAS, EOS, LYM, MON, and NEU) and platelets (PLT and MPV).
- To remove sources of technical and non-genetic biological variation, and thus increase our power to detect genetic associations, we removed out- liers exceeding four standard deviations from the mean of each trait in the overall study population.
- The assignment of low, but non-zero counts, allows these subjects to be in- cluded in the analysis, as it is known that these values are in fact (very) low..
- In the ancestry-combined, AA-specific, HL-specific, and EA-specific samples and 64% of variants had allele frequencies below 1%, respectively..
- In the discovery stage, we performed both univariate GWAS analysis for each of the eight traits and aSPU.
- In the univariate GWAS analysis, we tested the association of each genetic variant with the rank-based inverse-normally transformed re- sidual values in MEGA samples and in each individual study, respectively.
- (3) were available in the pooled MEGA result or were available in at least two non-MEGA studies when not available in the pooled MEGA result.
- These novel findings were examined in the publicly available summary statistics from the BCX (http://www.mhi-humangenetics.org/en/resources).
- As we know the association results for the overlapping samples in WHI and BioMe we can “invert” the fixed effect meta- analysis reported on the BCX website to obtain the results of all non-overlapping samples in BCX..
- At each known locus that reached genome-wide significance in the ancestry-combined meta-analysis (P<2E-9), we identified the lead variant with the lowest P value and defined a 2 Mb region centered on the lead variant.
- We included the genotype dos- age for the lead variant in each region as an additional covariate in the regression model.
- 0.05 in the ancestry-combined analysis were considered signifi- cant.
- Inde- pendent signals identified in the stepwise conditional analysis were also examined using this functional data- base.
- In addition, we examined our novel findings and their LD proxies, as well as the independent signals at previ- ously reported loci, in two comprehensive data sets com- bining chromatin accessibility data derived from ATAC- seq in hematopoesis-related cell types and GWAS results for various blood cell traits in the UKBB (EA partici- pants only, https://molpath.shinyapps.io/ShinyHeme/) [34] and the BCX Consortium (ancestrally diverse popu- lations) [23.
- WBC: White blood cell count.
- org/10.1186/s .
- The complete list of PAGE members can be found at http://www.pagestudy.org.
- Geno- type data quality control and quality assurance services were provided by the Genetic Analysis Center in the Biostatistics Department of the University of Washington, through support provided by the CIDR contract..
- https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/.
- http://www.mhi-humangenetics.org/en/resources/.
- https://doi.org/10.1016/j.jacc .
- https://doi.org/10.1093/aje/154.8.758..
- https://doi.org/10.1056/NEJMra071014..
- https://doi.org/1 0.1111/j x..
- https://doi.org/10.1513/.
- https://doi.org/10.1111/j x..
- doi.org/10.1001/archinte.166.2.188..
- doi.org/10.1038/s .
- https://doi.org/10.1111/.
- https://doi..
- org/10.1375/twin.2.4.250..
- https://doi.org/1 0.1371/journal.pgen.1002491..
- https://doi.org/10.1016/j..
- https://doi.org/10.1371/journal.pgen.1006760..
- https://doi.org/10.1016/j.ajhg .
- https://doi.org/10.1093/hmg/ddu401..
- org/10.1038/ng.2962..
- https://doi.org/10.1371/journal.pgen.1006925..
- https://doi.org/10.1038/.
- Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases.
- org/10.1038/s .
- doi.org/10.1016/j.cell .
- https://doi.org/10.1097/MOH..
- Prevalence of neutropenia in the U.S.
- https://doi.org/10.7326/.
- Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.
- https://doi.org/10.1371/journal.pgen.1000360..
- white blood cell count in the Health ABC and Jackson Heart studies.
- https://doi.org/10.1038/s .
- https://doi.org/1 0.1371/journal.pone.0167758..
- https://doi.org/10.1038/ejhg.201 5.269..
- https://doi.org/10.1371/journal..
- https://doi.org/10.1002/.
- https://doi.org/10.1126/science.1262110..
- https://doi.org/10.1016/j.cell .
- org/10.1002/cpt.805..
- TRIM28 is essential for erythroblast differentiation in the mouse.
- doi.org/10.1182/blood .
- https://doi.org/10.3389/fimmu .
- https://doi.org/10.1186/s .
- doi.org/10.1002/gepi.21931..
- org/10.1093/bioinformatics/btq340..
- https://doi.org/10.1371/journal.pone.0120758..
- https://doi.org/1 0.1038/ng.3367..
- https://doi.org/10.1136/jmedgenet .
- doi.org/10.1093/bioinformatics/btu703..
- https://doi.org/10.103 8/ng.3477..
- https://doi.org/10.1038/na ture14248.