Rare coding variants pinpoint genes that control human hematological traits

Mousas, Abdou; Ntritsos, Georgios; Chen, Ming-Huei; Song, Ci; Huffman, Jennifer E.; Tzoulaki, Ioanna; Elliott, Paul; Psaty, Bruce M.; Auer, Paul L.; Johnson, Andrew D.; Εvangelou, Εvangelos; Lettre, Guillaume; Reiner, Alexander P.

doi:10.1371/journal.pgen.1006925

Cited by 44 publications

(40 citation statements)

References 52 publications

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“…The identification of rare coding variants has successfully pinpointed candidate genes for many complex traits, including blood-cell phenotypes (Auer et al, 2014; Chami et al, 2016; Eicher et al, 2016; Justice et al, 2019; Marouli et al, 2017; Mousas et al, 2017; Tajuddin et al, 2016). Our trans-ethnic and non-EA ancestry-specific meta-analyses yielded 16 coding variants with minor allele frequency (MAF) <1% ( Table 1 and Supplementary Table 15 ).…”

Section: Resultsmentioning

confidence: 99%

Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

Chen

Raffield

Mousas

et al. 2020

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words) 13Most loci identified by GWAS have been found in populations of European ancestry (EA). In 14 trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 15 non-EA individuals, we identified 5,552 trait-variant associations at P<5x10 -9 , including 71 16 novel loci not found in EA populations. We also identified novel ancestry-specific variants not 17 found in EA, including an IL7 missense variant in South Asians associated with lymphocyte 18 count in vivo and IL7 secretion levels in vitro. Fine-mapping prioritized variants annotated as 19 functional, and generated 95% credible sets that were 30% smaller when using the trans-ethnic 20 as opposed to the EA-only results. We explored the clinical significance and predictive value of 21 trans-ethnic variants in multiple populations, and compared genetic architecture and the impact 22 of natural selection on these blood phenotypes between populations. Altogether, our results for 23 hematological traits highlight the value of a more global representation of populations in genetic 24 studies. 25 26 4 causal variants (Li and Keating, 2014). Since blood cells play a key role in pathogen invasion, 50 defense and inflammatory responses, hematologic-associated genetic loci are particularly 51 predisposed to be differentiated across ancestral populations as a result of population history and 52 local evolutionary selective pressures (Ding et al., 2013; Lo et al., 2011; Raj et al., 2013). Given 53 the essential role of blood cells in tissue oxygen delivery, inflammatory responses, atherosclerosis, 54 and thrombosis (Byrnes and Wolberg, 2017; Chu et al., 2010; Colin et al., 2014; Tajuddin et al., 55 2016), factors that contribute to such inter-population differences in blood-cell traits may also play 56 appreciable roles in the pathogenesis of chronic diseases and health disparities between 57 populations. 58 59 5 RESULTS 60 Trans-ethnic and ancestry-specific blood-cell traits genetic associations 61We analyzed genotype-phenotype associations at up to 45 million autosomal variants in 746,667 62 participants, including 184,424 individuals of non-EA descent, for 15 traits (Figure 1, 63 Supplementary Tables 1-4, and Methods). The association results of the EA-specific meta-64 analyses are reported separately in a companion paper. In the trans-ethnic meta-analyses, we 65 identified 5,552 trait-variant associations at P<5x10 -9 , which include 71 novel associations not 66 reported in the EA-specific manuscript ( Supplementary Table 5). Of the 5,552 trans-ethnic loci, 67 128 showed strong evidence of allelic effect heterogeneity across populations (Pancestry.hetero <5x10 -68 9 ) ( Supplementary Figure 1 and Supplementary Table 5). Ancestry-specific meta-analyses 69 revealed 28 novel trait-variant associations (Figure 1 and Supplementary Tables 6-10). 70However, 19 out of these 21 novel AFR-specific associations map to chromosome 1 and are 71 associated with WBC or neutrophil counts, therefore reflecting long-range associations due...

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Section: Resultsmentioning

confidence: 99%

Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

Chen

Raffield

Mousas

et al. 2020

Preprint

Self Cite

159

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“…First, these traits are important intermediate clinical phenotypes for a variety of cardiovascular, hematologic, oncologic, immunologic, and infectious diseases (11). Second, these traits have family-based heritability estimates in the range of 40-65% (12,13), and have been highly fruitful for gene-mapping with >2700 common and rare variants identified, though primarily in individuals of European ancestry (14)(15)(16)(17)(18)(19). Third, these traits remain under-studied in admixed AA and Hispanic/Latino populations, despite evidence for the existence of variants with distinct genetic architecture in AAs and Hispanics/Latinos (20)(21)(22).…”

Section: Resultsmentioning

confidence: 99%

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Kowalski¹,

Qian²,

Hou³

et al. 2019

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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 still limited. In addition to the limited inclusion of these populations in NIH. The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. We thank Rasheeda Williams and Margaret Ginoza for providing assistance with program coordination. The complete list of PAGE members can be found at

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“…In the present review, we focused our attention on genetic studies performed on large population sample sets with at least one replication analysis on a different cohort. Our selection finally included eight publications reporting PLT count-associated variants identified via different approaches, including genome-wide association studies (GWAS) [24][25][26][27][28][29], whole exome sequencing [30,31] and ExomeChip [32][33][34]. Table 1 reports PLT count-associated variants/genes described in at least two of these studies included in our analysis.…”

Section: Genetic Determinants and Non-genetic Variables Associated Wimentioning

confidence: 99%

Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero

Izzi

Bonaccio

Gaetano

et al. 2018

Journal of Thrombosis and Haemostasis

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Platelet count represents a useful tool in clinical practice to discriminate individuals at higher risk of bleeding. Less obvious is the role of platelet count variability within the normal range of distribution in shaping the individual's disease risk profile. Epidemiological studies have shown that platelet count in the adult general population is associated with a number of health outcomes related to hemostasis and thrombosis. However, recent studies are suggesting a possible role of this platelet index also as an independent risk factor. In this review of adult population studies, we will first focus on known genetic and non-genetic determinants of platelet number variability. Next, we will evaluate platelet count as a marker and/or a predictor of disease risk and its interaction with other risk factors. We will then discuss the role of platelet count variability within the normal distribution range as a contribution to disease and mortality risk. The possibility of considering platelet count as a simple, inexpensive indicator of increased risk of disease and death in general populations could open new opportunities to investigate novel platelet pathophysiological roles as well as therapeutic opportunities. Future studies should also consider platelet count, not only platelet function, as a modulator of disease and mortality risk.

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Rare coding variants pinpoint genes that control human hematological traits

Cited by 44 publications

References 52 publications

Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero

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