Genetic associations link hematopoietic traits and disease end-points, but most causal variants and genes underlying these relationships are unknown. Here, we used genetic colocalization to nominate loci and genes related to shared genetic signal for hematopoietic, cardiovascular, autoimmune, neuropsychiatric, and cancer phenotypes. Our aim was to identify colocalization sites for human traits among established genome-wide significant loci. Using genome-wide association study (GWAS) summary statistics, we determined loci where multiple traits colocalized at a false discovery rate < 5%. We then identified quantitative trait loci among colocalization sites to highlight related genes. In addition, we used Mendelian randomization analysis to further investigate certain trait relationships genome-wide. Our findings recapitulated developmental hematopoietic lineage relationships, identified loci that linked traits with causal genetic relationships, and revealed novel trait associations. Out of 2706 loci with genome-wide significant signal for at least 1 blood trait, we identified 1779 unique sites (66%) with shared genetic signal for 2+ hematologic traits. We could assign some sites to specific developmental cell types during hematopoiesis based on affected traits, including those likely to impact hematopoietic progenitor cells and/or megakaryocyte-erythroid progenitor cells. Through an expanded analysis of 70 human traits, we defined 2+ colocalizing traits at 2123 loci from an analysis of 9852 sites (22%) containing genome-wide significant signal for at least 1 GWAS trait. In addition to variants and genes underlying shared genetic signal between blood traits and disease phenotypes that had been previously related through Mendelian randomization studies, we defined loci and related genes underlying shared signal between eosinophil percentage and eczema. We also identified colocalizing signals in a number of clinically relevant coding mutations, including sites linking PTPN22 with Crohn’s disease, NIPA with coronary artery disease and platelet trait variation, and the hemochromatosis gene HFE with altered lipid levels. Finally, we anticipate potential off-target effects on blood traits related novel therapeutic targets, including TRAIL. Our findings provide a road map for gene validation experiments and novel therapeutics related to hematopoietic development, and offer a rationale for pleiotropic interactions between hematopoietic loci and disease end-points.

中文翻译：

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遗传共定位图谱指出了造血特征的共同调控位点和基因以及造血对疾病表型的贡献。


遗传关联将造血特征和疾病终点联系起来，但这些关系背后的大多数因果变异和基因尚不清楚。在这里，我们使用遗传共定位来提名与造血、心血管、自身免疫、神经精神和癌症表型的共享遗传信号相关的基因座和基因。我们的目标是在已建立的全基因组显着位点中确定人类特征的共定位位点。使用全基因组关联研究 (GWAS) 汇总统计，我们确定了多个性状共定位的位点，错误发现率 < 5%。然后，我们确定了共定位位点之间的数量性状基因座以突出相关基因。此外，我们使用孟德尔随机化分析来进一步研究全基因组范围内的某些性状关系。我们的研究结果概括了发育造血谱系关系，确定了将性状与因果遗传关系联系起来的基因座，并揭示了新的性状关联。在至少 1 个血液性状具有全基因组显着信号的 2706 个基因座中，我们鉴定了 1779 个独特位点 (66%) 具有 2 个以上血液性状的共享遗传信号。我们可以根据受影响的特征，将一些位点分配给造血过程中的特定发育细胞类型，包括那些可能影响造血祖细胞和/或巨核细胞-红系祖细胞的特征。通过对 70 个人类性状的扩展分析，我们通过对 9852 个位点 (22%) 的分析，在 2123 个位点定义了 2 个以上共定位性状，这些位点包含至少 1 个 GWAS 性状的全基因组显着信号。 除了之前通过孟德尔随机化研究相关的血液性状和疾病表型之间共享遗传信号的变异和基因之外，我们还定义了嗜酸性粒细胞百分比和湿疹之间共享信号的位点和相关基因。我们还在许多临床相关编码突变中发现了共定位信号，包括将 PTPN22 与克罗恩病、NIPA 与冠状动脉疾病和血小板性状变异相关的位点，以及与血脂水平改变相关的血色素沉着症基因 HFE。最后，我们预计对血液性状相关的新治疗靶点（包括 TRAIL）有潜在的脱靶影响。我们的研究结果为基因验证实验和与造血发育相关的新疗法提供了路线图，并为造血基因座和疾病终点之间的多效性相互作用提供了基本原理。