Dataset Information

Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program.

ABSTRACT: How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting. While informed by our experiences as researchers affiliated with the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, these recommendations are applicable to basic and translational genomic research in diverse populations with genome-wide data. Moving forward, considerable collaborative effort will be required to ensure that race, ethnicity, and ancestry are described and used appropriately to generate scientific knowledge that yields broad and equitable benefit.

SUBMITTER: Khan AT

PROVIDER: S-EPMC9481067 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program.

Khan Alyna T AT Gogarten Stephanie M SM McHugh Caitlin P CP Stilp Adrienne M AM Sofer Tamar T Bowers Michael L ML Wong Quenna Q Cupples L Adrienne LA Hidalgo Bertha B Johnson Andrew D AD McDonald Merry-Lynn N MN McGarvey Stephen T ST Taylor Matthew R G MRG Fullerton Stephanie M SM Conomos Matthew P MP Nelson Sarah C SC

Cell genomics 20220726 8

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic res ...[more]

PMID: 36119389

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Project description: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, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these 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 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (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.

Project description:Despite increasing diversity in research recruitment, research finding reporting by gender, race, ethnicity, and sex has remained up to the discretion of authors. This study developped and piloted tools to standardize the inclusive reporting of gender, race, ethnicity, and sex in health research. A modified Delphi approach was used to develop standardized tools for the inclusive reporting of gender, race, ethnicity, and sex in health research. Health research, social epidemiology, sociology, and medical anthropology experts from 11 different universities participated in the Delphi process. The tools were pilot tested on 85 health research manuscripts in top health research journals to determine inter-rater reliability of the tools. The tools each spanned five dimensions for both sex and gender as well as race and ethnicity: Author inclusiveness, Participant inclusiveness, Nomenclature reporting, Descriptive reporting, and Outcomes reporting for each subpopulation. The sex and gender tool had a median score of 6 and a range of 1-15 out of 16 possible points. The percent agreement between reviewers piloting the sex and gender tool was 82%. The interrater reliability or average Cohen's Kappa was 0.54 with a standard deviation of 0.33 demonstrating moderate agreement. The race and ethnicity tool had a median score of 1 and a range of 0-15 out of 16 possible points. Race and ethnicity were both reported in only 25.8% of studies evaluated. Most studies that reported race reported only the largest subgroups; White, Black, and Latinx. The percent agreement between reviewers piloting the race and ethnicity tool was 84 and average Cohen's Kappa was 0.61 with a standard deviation of 0.38 demonstrating substantial agreement. While the overall dimension scores were low (indicating low inclusivity), the interrater reliability measures indicated moderate to substantial agreement for the respective tools. Efforts in recruitment alone will not provide more inclusive literature without improving reporting.

Dataset Information

Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program.

Publications

Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program.

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