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1.
Hum Mol Genet ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34553764

RESUMO

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 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 GWAS 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 whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

2.
Am J Hum Genet ; 108(10): 1836-1851, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34582791

RESUMO

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.


Assuntos
Asma/epidemiologia , Biomarcadores/metabolismo , Dermatite Atópica/epidemiologia , Leucócitos/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Locos de Características Quantitativas , Asma/genética , Asma/metabolismo , Asma/patologia , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Prognóstico , Proteoma/análise , Proteoma/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Sequenciamento Completo do Genoma
4.
Nat Commun ; 12(1): 3505, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108472

RESUMO

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Predisposição Genética para Doença/genética , Adulto , Variação Biológica da População , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Exoma/genética , Genótipo , Humanos , Herança Multifatorial , Penetrância , Medição de Risco
5.
Am J Hum Genet ; 108(5): 874-893, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887194

RESUMO

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.


Assuntos
Eritrócitos/metabolismo , Eritrócitos/patologia , Estudo de Associação Genômica Ampla , National Heart, Lung, and Blood Institute (U.S.)/organização & administração , Fenótipo , Adulto , Idoso , Cromossomos Humanos Par 16/genética , Conjuntos de Dados como Assunto , Feminino , Edição de Genes , Variação Genética/genética , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade , Reprodutibilidade dos Testes , Estados Unidos
6.
Nat Metab ; 3(2): 228-243, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619380

RESUMO

Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.


Assuntos
Adiposidade/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Obesidade/genética , Adipócitos/metabolismo , Adipócitos Marrons/fisiologia , Adipócitos Brancos/fisiologia , Tecido Adiposo/metabolismo , Alelos , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Família Multigênica/genética , Obesidade/complicações , Medição de Risco , Transdução de Sinais/fisiologia
7.
PLoS Med ; 17(7): e1003196, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32692746

RESUMO

BACKGROUND: Melanocortin 4 receptor (MC4R) deficiency, caused by mutations in MC4R, is the most common cause of monogenic forms of obesity. However, these mutations have often been identified in small-scale, case-focused studies. Here, we assess the penetrance of previously reported MC4R mutations at a population level. Furthermore, we examine why some carriers of pathogenic mutations remain of normal weight, to gain insight into the mechanisms that control body weight. METHODS AND FINDINGS: We identified 59 known obesity-increasing mutations in MC4R from the Human Gene Mutation Database (HGMD) and Clinvar. We assessed their penetrance and effect on obesity (body mass index [BMI] ≥ 30 kg/m2) in >450,000 individuals (age 40-69 years) of the UK Biobank, a population-based cohort study. Of these 59 mutations, only 11 had moderate-to-high penetrance and increased the odds of obesity by more than 2-fold. We subsequently focused on these 11 mutations and examined differences between carriers of normal weight and carriers with obesity. Twenty-eight of the 182 carriers of these 11 mutations were of normal weight. Body composition of carriers of normal weight was similar to noncarriers of normal weight, whereas among individuals with obesity, carriers had a somewhat higher BMI than noncarriers (1.44 ± 0.07 standard deviation scores [SDSs] ± standard error [SE] versus 1.29 ± 0.001, P = 0.03), because of greater lean mass (1.44 ± 0.09 versus 1.15 ± 0.002, P = 0.002). Carriers of normal weight more often reported that, already at age 10 years, their body size was below average or average (72%) compared with carriers with obesity (48%) (P = 0.01). To assess the polygenic contribution to body weight in carriers of normal weight and carriers with obesity, we calculated a genome-wide polygenic risk score for BMI (PRSBMI). The PRSBMI of carriers of normal weight (PRSBMI = -0.64 ± 0.18) was significantly lower than of carriers with obesity (0.40 ± 0.11; P = 1.7 × 10-6), and tended to be lower than that of noncarriers of normal weight (-0.29 ± 0.003; P = 0.05). Among carriers, those with a low PRSBMI (bottom quartile) have an approximately 5-kg/m2 lower BMI (approximately 14 kg of body weight for a 1.7-m-tall person) than those with a high PRS (top quartile). Because the UK Biobank population is healthier than the general population in the United Kingdom, penetrance may have been somewhat underestimated. CONCLUSIONS: We showed that large-scale data are needed to validate the impact of mutations observed in small-scale and case-focused studies. Furthermore, we observed that despite the key role of MC4R in obesity, the effects of pathogenic MC4R mutations may be countered, at least in part, by a low polygenic risk potentially representing other innate mechanisms implicated in body weight regulation.


Assuntos
Mutação , Obesidade/genética , Receptor Tipo 4 de Melanocortina/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Composição Corporal/genética , Índice de Massa Corporal , Peso Corporal/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Penetrância , Reino Unido
8.
Am J Hum Genet ; 99(1): 8-21, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346685

RESUMO

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.


Assuntos
Eritrócitos/citologia , Eritropoese/genética , Exoma/genética , Pleiotropia Genética , Variação Genética/genética , Genótipo , Afro-Americanos/genética , Desequilíbrio Alélico , Índices de Eritrócitos , Eritrócitos/metabolismo , Frequência do Gene , Hematócrito , Hemoglobinas/genética , Humanos , Locos de Características Quantitativas/genética
9.
Am J Hum Genet ; 99(1): 40-55, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346686

RESUMO

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.


Assuntos
Plaquetas/metabolismo , Exoma/genética , Variação Genética/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Volume Plaquetário Médio , Contagem de Plaquetas
10.
Am J Hum Genet ; 99(1): 22-39, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346689

RESUMO

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 âˆ¼157,622 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.


Assuntos
Exoma/genética , Loci Gênicos/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/genética , Leucócitos/citologia , Contagem de Células Sanguíneas , Humanos , Controle de Qualidade
11.
Can J Cardiol ; 30(12): 1655-61, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25448463

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure that may require heart transplantation. Approximately one third of DCM cases are familial. Next-generation DNA sequencing of large panels of candidate genes (ie, targeted sequencing) or of the whole exome can rapidly and economically identify pathogenic mutations in familial DCM. METHODS: We recruited 64 individuals from 26 DCM families followed at the Montreal Heart Institute Cardiovascular Genetic Center and sequenced the whole exome of 44 patients and 2 controls. Both affected and unaffected family members underwent genotyping for segregation analysis. RESULTS: We found 2 truncating mutations in BAG3 in 4 DCM families (15%) and confirmed segregation with disease status by linkage (log of the odds [LOD] score = 3.8). BAG3 nonsense mutations conferred a worse prognosis as evidenced by a younger age of clinical onset (37 vs 48 years for carriers and noncarriers respectively; P = 0.037). We also found truncating mutations in TTN in 5 families (19%). Finally, we identified potential pathogenic mutations for 9 DCM families in 6 candidate genes (DSP, LMNA, MYH7, MYPN, RBM20, and TNNT2). We still need to confirm several of these mutations by segregation analysis. CONCLUSIONS: Screening an extended panel of 41 candidate genes allowed us to identify probable pathogenic mutations in 69% of families with DCM in our cohort of mostly French-Canadian patients. We confirmed the prevalence of TTN nonsense mutations in DCM. Furthermore, to our knowledge, we are the first to present an association between nonsense mutations in BAG3 and early-onset DCM.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatia Dilatada/genética , Códon sem Sentido , DNA/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idade de Início , Proteínas Reguladoras de Apoptose/metabolismo , Canadá/epidemiologia , Cardiomiopatia Dilatada/etnologia , Cardiomiopatia Dilatada/metabolismo , Análise Mutacional de DNA , Feminino , França/etnologia , Ligação Genética , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
12.
Nat Genet ; 46(6): 629-34, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777453

RESUMO

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10(-13)). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10(-7)) and WBC count (P = 3.1 × 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.


Assuntos
Hemoglobinas/genética , Contagem de Leucócitos , Neutropenia/congênito , Contagem de Plaquetas , Receptores de Interleucina-8B/genética , Adulto , Idoso , Quimiotaxia , Síndrome Congênita de Insuficiência da Medula Óssea , Exoma , Feminino , Mutação da Fase de Leitura , Estudo de Associação Genômica Ampla , Genótipo , Hematócrito , Hematopoese , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neutropenia/genética , Linhagem
13.
Genes (Basel) ; 5(1): 51-64, 2014 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-24705286

RESUMO

Genome-wide association studies (GWAS) have identified reproducible genetic associations with hundreds of human diseases and traits. The vast majority of these associated single nucleotide polymorphisms (SNPs) are non-coding, highlighting the challenge in moving from genetic findings to mechanistic and functional insights. Nevertheless, large-scale (epi)genomic studies and bioinformatic analyses strongly suggest that GWAS hits are not randomly distributed in the genome but rather pinpoint specific biological pathways important for disease development or phenotypic variation. In this review, we focus on GWAS discoveries for the three main blood cell types: red blood cells, white blood cells and platelets. We summarize the knowledge gained from GWAS of these phenotypes and discuss their possible clinical implications for common (e.g., anemia) and rare (e.g., myeloproliferative neoplasms) human blood-related diseases. Finally, we argue that blood phenotypes are ideal to study the genetics of complex human traits because they are fully amenable to experimental testing.

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