Genetic Regulation of Gene Expression in Hispanic/Latino Cord Blood Samples - ABSTRACT Understanding the genetic regulation of gene expression, such as through the identification of expression quantitative trait loci (eQTLs), is essential for the interpretation of genome-wide association studies (GWAS) and pinpointing genetic effects on human traits and diseases that are likely to be causal. Early-life measures of gene expression may provide more power to detect eQTLs and more accurate effect estimates of eQTLs due to the minimization of environmental effects. Measures of early-life gene expression may also improve the performance of transcriptome-wide association studies (TWAS), which use the genetically determined component of gene expression to identify genes associated with disease risk, both for early- and adult-onset traits. However, there is an extreme paucity of data on early-life gene expression, and little understanding of whether eQTLs determined in early-life may explain more disease heritability than adult-derived eQTLs. Moreover, to our knowledge, there are no studies of gene expression in newborns of Hispanic/Latino ethnicity, which may exacerbate disparities in the discovery of genetic-disease associations that impact this population. This is of interest for certain phenotypes such as asthma, for which Hispanic/Latino children have an increased risk compared with non-Hispanic White children. Leveraging the unique collection of umbilical cord blood (CB) samples in the NHLBI BioLINCC Biorepository, our proposal aims to understand the genetic architecture of early- life gene expression in a Hispanic/Latino newborn population, and to discover novel insights into the etiologies of early-life and adult-onset traits in Hispanics/Latinos using CB-derived TWAS models. In our first aim, we will generate new mRNA sequencing and genome-wide SNP array data from 400 Hispanic/Latino CB samples in BioLINCC, then calculate the cis-heritability of gene expression and examine differences by local and global genetic ancestry. We will also assess the effects of sex and birth-related variables (e.g. mode of delivery) on variation in gene expression in CB. In our second aim, we will identify eQTLs as well as splice-eQTLs (sQTLs) – genetic variants associated with alternative splicing – and conduct fine-mapping to pinpoint causal variants. We will also examine potential differences in eQTL and sQTL effects by ancestry, age, and sex. Finally, in our third aim we will develop TWAS models in the Hispanic/Latino CB samples to identify susceptibility genes associated with early-life and adult-onset traits in Hispanic/Latino populations. Specifically, we will use summary statistics from existing GWAS to conduct TWAS on childhood asthma, blood cell traits, coronary artery disease, and clonal hematopoiesis. We will also evaluate the performance of CB-derived TWAS models compared with models developed in existing data from older Hispanics/Latinos and in adults of predominantly European ancestry. Our innovative approach that capitalizes on the availability of stored CB in NHLBI BioLINCC will provide novel insights into gene expression variation in CB, will help to elucidate the genetic architecture of complex traits in Hispanic/Latino populations, and will provide a valuable new resource for the research community.
