Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program

Abstract

Whole genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these newly discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3bp indel p.Lys2169del (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis [OMIM 194380], associated with higher MCHC. In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically-diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

“…Most attention on the potential of DNA sequencing to personalise medicine focuses on discovery of novel genetic causes of disease,[1,43] and development of polygenic risk scores from large-scale studies identifying common variation across blocks of genes co-inherited in linkage disequilibrium[44] that can direct attention to novel cis- regulatory elements. [44,45] The presented approach offers an accelerated route to the clinic, by proceeding from genes already known to have functional impact in processes potentially relevant to the patient. While a small proportion of rare deleterious variants cause recognised human diseases, most do not, either because they are not present at sufficient zygosity, or because they are not in an appropriate patient/environment milieu to be exposed above an essentially compensated perturbation to normal physiology.…”