The Polygenic and Monogenic Basis of Blood Traits and Diseases
Vuckovic D., Bao EL., Akbari P., Lareau CA., Mousas A., Jiang T., Chen M-H., Raffield LM., Tardaguila M., Huffman JE., Ritchie SC., Megy K., Ponstingl H., Penkett CJ., Albers PK., Wigdor EM., Sakaue S., Moscati A., Manansala R., Lo KS., Qian H., Akiyama M., Bartz TM., Ben-Shlomo Y., Beswick A., Bork-Jensen J., Bottinger EP., Brody JA., van Rooij FJA., Chitrala KN., Cho K., Choquet H., Correa A., Danesh J., Di Angelantonio E., Dimou N., Ding J., Elliott P., Esko T., Evans MK., Felix SB., Floyd JS., Broer L., Grarup N., Guo MH., Greinacher A., Haessler J., Hansen T., Howson JMM., Huang W., Jorgenson E., Kacprowski T., Kähönen M., Kamatani Y., Kanai M., Karthikeyan S., Koskeridis F., Lange LA., Lehtimäki T., Linneberg A., Liu Y., Lyytikäinen L-P., Manichaikul A., Matsuda K., Mohlke KL., Mononen N., Murakami Y., Nadkarni GN., Nikus K., Pankratz N., Pedersen O., Preuss M., Psaty BM., Raitakari OT., Rich SS., Rodriguez BAT., Rosen JD., Rotter JI., Schubert P., Spracklen CN., Surendran P., Tang H., Tardif J-C., Ghanbari M., Völker U., Völzke H., Watkins NA., Weiss S., Cai N., Kundu K., Watt SB., Walter K., Zonderman AB., Wilson PWF., Li Y., Loos RJF., Knight J., Georges M., Stegle O., Evangelou E., Okada Y., Roberts DJ., Inouye M., Johnson AD., Auer PL., Astle WJ., Reiner AP., Butterworth AS., Ouwehand WH., Lettre G., Sankaran VG., Soranzo N.
SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
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Michelle Fernandes
Clinical Lecturer & MRC Clinical Research Training Fellow
