The Polygenic and Monogenic Basis of Blood Traits and Diseases

Abstract

Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range 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 traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease

“…We performed 2‐sample MR using the TwoSampleMR R package 22,23 . For the exposure instrument, we used summary statistics from the largest published GWAS on blood cell traits 24 . This GWAS of 408,112 European UKB participants used as its outcome measure the absolute lymphocyte count which was adjusted for covariates (age, sex, principal components, and study‐specific factors) and rank inverse‐normalized.…”

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

“…While the omnigenic model is broadly consistent with observations on cis and trans heritability of expression ( Liu et al, 2019 ), it has been difficult to evaluate the model in detail because for most diseases and other traits we know little in advance about which genes are likely to be directly involved in disease biology. Recent efforts to systematically nominate core genes have primarily relied upon associations identified in rare, monogenic disorders ( Vuckovic et al, 2020 ); while promising, such approaches are inherently limited by the ability to discover rare gene-disease associations, which can depend upon a number of factors. Furthermore, we still have highly incomplete information about cellular regulatory networks and trans-eQTLs.…”

Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

“…Therefore, the therapeutic potential of editing a GWAS locus not only depends on finding the causal SNPs per se but rather in understanding the elements and genes impacted which themselves could constitute the ultimate therapeutic target. In contrast to common variants of modest effect size, low-frequency or rare variants (MAF < 5%) uncovered by GWAS, especially those leading to loss-of-function, usually exhibit a relatively large phenotypic impact [ 122 ]. For example, carriers with inactivating mutations on PCSK9 were found to have markedly lower LDL cholesterol level and CAD risk, which led to the discovery of two FDA-approved monoclonal antibodies [ 123 ].…”