We used resequencing and genotyping in African Americans with sickle cell anemia (SCA) to characterize associations with fetal hemoglobin (HbF) levels at the BCL11A, HBS1L-MYB and β-globin loci. Fine-mapping of HbF association signals at these loci confirmed seven SNPs with independent effects and increased the explained heritable variation in HbF levels from 38.6% to 49.5%. We also identified rare missense variants that causally implicate MYB in HbF production.

Red blood cell, white blood cell, and platelet measures, including their count, sub-type and volume, are important diagnostic and prognostic clinical parameters for several human diseases. To identify novel loci associated with hematological traits, and compare the architecture of these phenotypes between ethnic groups, the CARe Project genotyped 49,094 single nucleotide polymorphisms (SNPs) that capture variation in ~2,100 candidate genes in DNA of 23,439 Caucasians and 7,112 African Americans from five population-based cohorts. We found strong novel associations between erythrocyte phenotypes and the glucose-6 phosphate dehydrogenase (G6PD) A-allele in African Americans (rs1050828, P < 2.0 × 10−13, T-allele associated with lower red blood cell count, hemoglobin, and hematocrit, and higher mean corpuscular volume), and between platelet count and a SNP at the tropomyosin-4 (TPM4) locus (rs8109288, P = 3.0 × 10−7 in Caucasians; P = 3.0 × 10−7 in African Americans, T-allele associated with lower platelet count). We strongly replicated many genetic associations to blood cell phenotypes previously established in Caucasians. A common variant of the α-globin (HBA2-HBA1) locus was associated with red blood cell traits in African Americans, but not in Caucasians (rs1211375, P < 7 × 10−8, A-allele associated with lower hemoglobin, mean corpuscular hemoglobin, and mean corpuscular volume). Our results show similarities but also differences in the genetic regulation of hematological traits in European- and African-derived populations, and highlight the role of natural selection in shaping these differences.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage III/IV disease, driven by *

BACKGROUND African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs. OBJECTIVES This study assessed the APOL1 risk alleles’ association with blood pressure traits in AAs. METHODS The discovery cohort included 5,204 AA participants from Mount Sinai’s BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles’ association with blood pressure–related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta-analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate. RESULTS There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [pcom] = 1.9 × 10−5). APOL1 risk alleles were associated with overall SBP (pcom = 7.0 × 10−8) and diastolic blood pressure (pcom = 2.8 × 10−4). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 ± 0.44 mm Hg (pcom = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range. CONCLUSIONS APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model.

Key Points Using genome-wide association study, we found the first replicated genetic association with acute chest syndrome in sickle cell disease patients. The locus identified includes COMMD7, a gene highly expressed in the lung that interacts with NFκB to control inflammatory responses.