Dataset Information

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.

ABSTRACT: Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

SUBMITTER: Little A

PROVIDER: S-EPMC8825339 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.

Little Amarise A Hu Yao Y Sun Quan Q Jain Deepti D Broome Jai J Chen Ming-Huei MH Thibord Florian F McHugh Caitlin C Surendran Praveen P Blackwell Thomas W TW Brody Jennifer A JA Bhan Arunoday A Chami Nathalie N de Vries Paul S PS Ekunwe Lynette L Heard-Costa Nancy N Hobbs Brian D BD Manichaikul Ani A Moon Jee-Young JY Preuss Michael H MH Ryan Kathleen K Wang Zhe Z Wheeler Marsha M Yanek Lisa R LR Abecasis Goncalo R GR Almasy Laura L Beaty Terri H TH Becker Lewis C LC Blangero John J Boerwinkle Eric E Butterworth Adam S AS Choquet Hélène H Correa Adolfo A Curran Joanne E JE Faraday Nauder N Fornage Myriam M Glahn David C DC Hou Lifang L Jorgenson Eric E Kooperberg Charles C Lewis Joshua P JP Lloyd-Jones Donald M DM Loos Ruth J F RJF Min Yuan-I YI Mitchell Braxton D BD Morrison Alanna C AC Nickerson Deborah A DA North Kari E KE O'Connell Jeffrey R JR Pankratz Nathan N Psaty Bruce M BM Vasan Ramachandran S RS Rich Stephen S SS Rotter Jerome I JI Smith Albert V AV Smith Nicholas L NL Tang Hua H Tracy Russell P RP Conomos Matthew P MP Laurie Cecelia A CA Mathias Rasika A RA Li Yun Y Auer Paul L PL Thornton Timothy T Reiner Alexander P AP Johnson Andrew D AD Raffield Laura M LM

Human molecular genetics 20220201 3

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We ident ...[more]

PMID: 34553764

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Project description:Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Project description:BackgroundRisk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies.MethodsThe 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants).ResultsSingle variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P=7.4×10-14) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P=1.6×10-14), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P=1.8×10-6 with the secondary filter), while SERPINC1 did not (minimum P=4.4×10-5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1, became significant (P=4.4×10-7 using all missense variants with minor allele frequency <0.0005).ConclusionsHere, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

Dataset Information

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.

Publications

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.

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