Several large-scale whole genome sequencing (WGS) and omics efforts are underway. Although these
programs are making strides towards including ancestrally diverse populations, there is still a notable gap in
analyses of these data that leverage diversity to empower discovery and improve our understanding of
genotypic and phenotypic architecture across all populations. Substantial European bias persists in ongoing
large scale WGS and omics efforts. Differences in genetic variation among ancestrally diverse groups are
well-known, and although data are very limited, gene expression, methylation, and metabolites also differ
among ancestrally diverse populations. The PAGE Study has been continuously funded by the NIH since 2008
to study genomic variation to advance our understanding of population architecture of complex genetic traits
and diseases, particularly in the presence of ancestral diversity. We have established PAGE at the forefront of
discovery and fine-mapping across 40 primary and >200 secondary complex traits and diseases in ancestrally
diverse populations, and have led the way in array (e.g. the Multi-Ethnic Global Array, Global Screening Array)
and statistical methods development specific to these diverse populations. Additionally, PAGE has served as a
valuable resource to the scientific community, placing a high priority on quickly disseminating allele frequency
data, GWAS summary statistics, study findings, and analytical software. PAGE Phase III (PAGE III) will include
existing genetics and genomics data from more than 120,000 diverse individuals from six well characterized
cohorts/biobanks. In PAGE III, we propose to extend and continue our invaluable work to date to 1) identify
and characterize genetic variants that influence complex traits and diseases in ancestrally diverse individuals
using both WGS data (n=>50,000) and imputed genotyping data (n=124,000), 2) integrate information on
sequence variation and omics to better understand the genetic underpinnings of complex traits in the diverse
PAGE participants, and 3) characterize biological pathways underlying disease risk both within and between
populations. For Aim 1, we will use recently generated sequence data to impute the largest sample of diverse
participants every considered for the genetics of complex traits. For Aim 2, we will use newly existing data to
impute gene expression, DNA methylation and metabolomics data into the remainder of PAGE samples, which
will involve both extension and development of current methodology to ensure suitability for ancestrally diverse
populations. Aim 3 will focus on integration of all omics data to inform discovery of novel pathways and the
genetic basis of complex diseases and elucidate the molecular drivers of disease etiologies across diverse
PAGE populations. As a continuation of our ground-breaking highly-successful work in PAGE over the last
decade, our proposal offers major advances towards understanding the genetic and genomic components
underlying biological mechanisms of disease, and translational medicine in adversely affected and
understudied diverse populations.