Red blood cells, white blood cells, and platelets are important for the clinical diagnosis of intrinsic blood cell and
hematopoietic disorders, and also as predictors of various heart, lung, and blood disease outcomes. Moreover,
hematologic quantitative traits are highly heritable and serve as a model system for studying the genetic
architecture of complex traits. While significant strides in understanding the genetic basis of hematological traits
have been made over the past decade, the wealth of whole genome sequencing (WGS) data from emerging
resources such as the NHLBI Trans-Omics for Precision Medicine (TOPMed) program provides an
unprecedented opportunity to gain further insight in several key areas, including the role of structural variants
(SVs). While a few common SVs (e.g., α-globin) are known to be associated with blood cell traits, a more
systematic and agnostic genome-wide search for SVs in large samples is required to identify new biology. The
centralized availability of deeply sequenced DNA from the NHLBI TOPMed and the NHGRI Centers for Common
Disease Genomics (CCDG) programs, along with genome-wide data from UK Biobank and other cohorts, allows
for full characterization of SVs genome-wide at population-scale. By improving the accuracy of genome-wide SV
calling for WGS data as implemented in our new Genvisis software package and by validating candidate causal
SVs using state-of-the-art gene-editing technologies in hematopoietic cells, our interdisciplinary approach will
facilitate the translation of genetic association findings into mechanistic insights, discover new biology underlying
hematopoiesis, and ultimately identify factors that account for individual differences in pathobiology or response
to treatments. In Aim 1, using WGS data from TOPMed and CCDG participants, we will apply novel methodology
to generate high-quality and more accurate SV calls than the SV calling algorithms currently available for both
WGS and existing array data. In Aim 2, we will use the newly generated SV calls to conduct single-variant and
gene-based segmental association analyses of SVs with blood cell traits and related clinical outcomes in up to
570,319 participants. Association findings will be replicated in up to 760,000 participants in populations/studies
not used in the discovery phase. SVs that are significantly associated with blood cell traits will subsequently be
tested for association with other blood disorders including clonal hematopoiesis of indeterminate potential (CHIP)
and VTE. In Aim 3, targeted long-range sequencing will be performed in selected samples to precisely localize
newly identified blood trait-associated SVs in complex genomic regions. We will also perform functional genomic
annotation of replicated blood cell trait-SV associations followed by state-of-the art gene-editing approaches to
understand novel mechanisms underlying genetic regulation of hematopoiesis. This model integrative approach
to advancing precision medicine research in heart, lung, and blood diseases will demonstrate for the first time
the role of SVs in the genetic architecture of hematologic traits and contribute to a better understanding of
hematopoiesis and pave the way for new research into Precision Medicine for blood diseases.