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Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
Erythrocyte and leukocyte blood counts are heritable traits (estimated heritability of 0.40-0.90 (refs. 1-3) and 0.14-0.40 (ref. 4), respectively) that reflect core physiological functions of oxygen-carrying capacity and antimicrobial activity. Peripheral blood cell counts are commonly measured in the clinical setting to diagnose and monitor therapy for many acute and chronic conditions, such as infection or anemia. Abnormalities in these clinical measures often reflect primary hematologic disease, blood loss, or inflammation. Between-individual differences in erythrocyte traits, total WBC counts, and neutrophil counts have been associated with risk of cardiovascular diseases and all-cause mortality5-7.
Previous genome-wide association studies (GWAS) have defined over 100 loci influencing erythrocyte traits8-12 and leukocyte counts8,13,14. However, few studies have systematically evaluated the contribution 867of coding variation, particularly variants at low frequency in the general population15,16. Recently completed exome sequencing in diverse populations has led to international collaboration and creation of a genome-wide catalog of low-frequency coding variants. We undertook a large-scale study of erythrocyte and leukocyte traits in up to 52,531 individuals of European, African, and Hispanic ancestry to evaluate the impact of both low-frequency and common variants assayed by the Illumina HumanExome BeadChip, also referred to as the exome chip.
RESULTS
Study samples
In the discovery stage, we analyzed erythrocyte traits (hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular...