Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos

Abstract

Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

“…Due to the relatively small number of Hispanic/Latino individuals with blood cell trait data in TOPMed freeze 5b (n~1,080), including only one heterozygote carrier of rs11549407 in those with blood cell traits measured, we were unable to perform a well-powered replication of the association of rs11549407 with HGB and HCT. Moderate anemia is known to occur in some individuals with thalassemia minor, however, concordant with our results(38).The association of the HBB missense (p.Glu7Lys) variant 11:5227003:C:T or rs33930165 with higher total WBC (β =0.28 and p=8.1x10 -12 ) among AA was unexpected; rs33930165 has been associated with red blood cell indices such as mean corpuscular hemoglobin concentration(20) but not with white blood cell traits. Because of the higher allele frequency of this variant and also the larger number of AA samples (n=6,743) in TOPMed freeze 5b, we were able to replicate this HBB rs33930165 association with total WBC in an independent sample (β=0.27 and p=4.6x10 -4 ) of AA individuals.…”

“…Second, these traits have family-based heritability estimates in the range of 40-65% (12,13), and have been highly fruitful for gene-mapping with >2700 common and rare variants identified, though primarily in individuals of European ancestry (14)(15)(16)(17)(18)(19). Third, these traits remain under-studied in admixed AA and Hispanic/Latino populations, despite evidence for the existence of variants with distinct genetic architecture in AAs and Hispanics/Latinos (20)(21)(22). For example, while hundreds of variants identified in genome-wide association studies (GWAS) of WBC in individuals of European descent explain only ~7% of array heritability, the African specific Duffy null variant DARC rs2814778 alone accounts for 15-20% of population-level WBC variability in AAs (23).…”

“…We first evaluated association statistics for variants previously associated with HGB, HCT, or WBC count in AA and Hispanic/Latino populations (summarized in Table S10). We assembled a list of 24 AA and 13 Hispanic/Latino previously identified autosomal signals from prior published GWAS or exome-based studies (1, 19,20,[24][25][26][27][28][29][30]. Our lists excluded variants reported in multi-ethnic cohorts or meta-analysis including individuals of non-AA or non-Hispanic/Latino ancestry to guard against the scenario that the reported signals were driven predominantly by individuals of European or Asian ancestry.…”

Generalizing polygenic risk scores from Europeans to Hispanics/Latinos

“…Sample sizes ranged from 11,809 to 12,705. GWASs for blood count traits in the HCHS/SOL were reported in Hodonsky et al (2017), Jain et al (2017), and Schick et al (2016), and GWASs for blood pressure (BP) traits were reported in Sofer, Wong, et al (2017).…”

Generalization and fine mapping of red blood cell trait genetic associations to multi‐ethnic populations: The PAGE study

“…With regard to bioinformatic characterization for functional candidate SNP evaluation, eQTL analysis—while insufficient as the sole determinant of tissue specificity—is an important component for ascertaining functional status of candidate variants. Finally, the Metabochip design emphasized regions identified for cardiometabolic traits, so overlap with RBC-trait associations was coincidental; we therefore could not examine generalization or fine-mapping in several well established RBC trait associations, including HBS1L/MYB , LUC7L/ITGF3, HBA1/2 , and HBB 17; 18; 21; 74 .…”