Dataset Information

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

ABSTRACT: White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ?157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

SUBMITTER: Tajuddin SM

PROVIDER: S-EPMC5005433 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

Tajuddin Salman M SM Schick Ursula M UM Eicher John D JD Chami Nathalie N Giri Ayush A Brody Jennifer A JA Hill W David WD Kacprowski Tim T Li Jin J Lyytikäinen Leo-Pekka LP Manichaikul Ani A Mihailov Evelin E O'Donoghue Michelle L ML Pankratz Nathan N Pazoki Raha R Polfus Linda M LM Smith Albert Vernon AV Schurmann Claudia C Vacchi-Suzzi Caterina C Waterworth Dawn M DM Evangelou Evangelos E Yanek Lisa R LR Burt Amber A Chen Ming-Huei MH van Rooij Frank J A FJ Floyd James S JS Greinacher Andreas A Harris Tamara B TB Highland Heather M HM Lange Leslie A LA Liu Yongmei Y Mägi Reedik R Nalls Mike A MA Mathias Rasika A RA Nickerson Deborah A DA Nikus Kjell K Starr John M JM Tardif Jean-Claude JC Tzoulaki Ioanna I Velez Edwards Digna R DR Wallentin Lars L Bartz Traci M TM Becker Lewis C LC Denny Joshua C JC Raffield Laura M LM Rioux John D JD Friedrich Nele N Fornage Myriam M Gao He H Hirschhorn Joel N JN Liewald David C M DC Rich Stephen S SS Uitterlinden Andre A Bastarache Lisa L Becker Diane M DM Boerwinkle Eric E de Denus Simon S Bottinger Erwin P EP Hayward Caroline C Hofman Albert A Homuth Georg G Lange Ethan E Launer Lenore J LJ Lehtimäki Terho T Lu Yingchang Y Metspalu Andres A O'Donnell Chris J CJ Quarells Rakale C RC Richard Melissa M Torstenson Eric S ES Taylor Kent D KD Vergnaud Anne-Claire AC Zonderman Alan B AB Crosslin David R DR Deary Ian J IJ Dörr Marcus M Elliott Paul P Evans Michele K MK Gudnason Vilmundur V Kähönen Mika M Psaty Bruce M BM Rotter Jerome I JI Slater Andrew J AJ Dehghan Abbas A White Harvey D HD Ganesh Santhi K SK Loos Ruth J F RJ Esko Tõnu T Faraday Nauder N Wilson James G JG Cushman Mary M Johnson Andrew D AD Edwards Todd L TL Zakai Neil A NA Lettre Guillaume G Reiner Alex P AP Auer Paul L PL

American journal of human genetics 20160623 1

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based ...[more]

PMID: 27346689

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Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Project description:The eastern Africa region, Ethiopia and its surroundings, is considered as the center of origin and diversity for sorghum, and has contributed to global sorghum genetic improvement. The germplasm from this region harbors enormous genetic variation for various traits but little is known regarding the genetic architecture of most traits. Here, 1425 Ethiopian landrace accessions were phenotyped under field conditions for presence or absence of awns, panicle compactness and shape, panicle exsertion, pericarp color, glume cover, plant height and smut resistance under diverse environmental conditions in Ethiopia. In addition, F1 hybrids obtained from a subset of 1341 accessions crossed to an A1 cytoplasmic male sterile line, ATx623, were scored for fertility/sterility reactions. Subsequently, genotyping-by-sequencing generated a total of 879,407 SNPs from which 72,190 robust SNP markers were selected after stringent quality control (QC). Pairwise distance-based hierarchical clustering identified 11 distinct groups. Of the genotypes assigned to either one of the 11 sub-populations, 65% had high ancestry membership coefficient with the likelihood of more than 0.60 and the remaining 35% represented highly admixed accessions. A genome-wide association study (GWAS) identified loci and SNPs associated with aforementioned traits. GWAS based on compressed mixed linear model (CMLM) identified SNPs with significant association (FDR ≤ 0.05) to the different traits studied. The percentage of total phenotypic variation explained with significant SNPs across traits ranged from 2 to 43%. Candidate genes showing significant association with different traits were identified. The sorghum bHLH transcription factor, ABORTED MICROSPORES was identified as a strong candidate gene conditioning male fertility. Notably, sorghum CLAVATA1 receptor like kinase, known for regulation of plant growth, and the ETHYLENE RESPONSIVE TRANSCRIPTION FACTOR gene RAP2-7, known to suppress transition to flowering, were significantly associated with plant height. In addition, the YELLOW SEED1 like MYB transcription factor and TANNIN1 showed strong association with pericarp color validating previous observations. Overall, the genetic architecture of natural variation representing the complex Ethiopian sorghum germplasm was established. The study contributes to the characterization of genes and alleles controlling agronomic traits, and will serve as a source of markers for molecular breeding.

Dataset Information

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

Publications

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

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