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1.
Commun Biol ; 5(1): 386, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449187

RESUMO

Actinic keratosis (AK) is a common precancerous cutaneous neoplasm that arises on chronically sun-exposed skin. AK susceptibility has a moderate genetic component, and although a few susceptibility loci have been identified, including IRF4, TYR, and MC1R, additional loci have yet to be discovered. We conducted a genome-wide association study of AK in non-Hispanic white participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (n = 63,110, discovery cohort), with validation in the Mass-General Brigham (MGB) Biobank cohort (n = 29,130). We identified eleven loci (P < 5 × 10-8), including seven novel loci, of which four novel loci were validated. In a meta-analysis (GERA + MGB), one additional novel locus, TRPS1, was identified. Genes within the identified loci are implicated in pigmentation (SLC45A2, IRF4, BNC2, TYR, DEF8, RALY, HERC2, and TRPS1), immune regulation (FOXP1 and HLA-DQA1), and cell signaling and tissue remodeling (MMP24) pathways. Our findings provide novel insight into the genetics and pathogenesis of AK susceptibility.


Assuntos
Ceratose Actínica , Neoplasias Cutâneas , Adulto , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Humanos , Ceratose Actínica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Neoplasias Cutâneas/genética
2.
Ophthalmology ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35031440

RESUMO

PURPOSE: To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. DESIGN: A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. PARTICIPANTS: A total of 574 cases with PG or PDS and 52 627 controls of European descent. METHODS: Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. MAIN OUTCOME MEASURES: The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. RESULTS: Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10-7). CONCLUSIONS: Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

3.
Hum Mol Genet ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022708

RESUMO

Inguinal hernias are some of the most frequently diagnosed conditions in clinical practice and inguinal hernia repair is the most common procedure performed by general surgeons. Studies of inguinal hernias in non-European populations are lacking, though it is expected that such studies could identify novel loci. Further, the cumulative lifetime incidence of inguinal hernia is nine times greater in men than women, however it is not clear why this difference exists. We conducted a genome-wide association meta-analysis of inguinal hernia risk across 513 120 individuals (35 774 cases and 477 346 controls) of Hispanic/Latino, African, Asian, and European descent, with replication in 728 418 participants (33 491 cases and 694 927 controls) from the 23andMe, Inc dataset. We identified 63 genome-wide significant loci (P < 5x10-8), including 41 novel. Ancestry-specific analyses identified two loci (LYPLAL1-AS1/SLC30A10 and STXBP6-NOVA1) in African ancestry individuals. Sex-stratified analyses identified two loci (MYO1D and ZBTB7C) that are specific to women, and four (EBF2, EMX2/RAB11FIP2, VCL and FAM9A/FAM9B) that are specific to men. Functional experiments demonstrated that several of the associated regions (EFEMP1 and LYPLAL1-SLC30A10) function as enhancers and show differential activity between risk and reference alleles. Our study highlights the importance of large-scale genomic studies in ancestrally diverse populations for identifying ancestry-specific inguinal hernia susceptibility loci and provides novel biological insights into inguinal hernia etiology.

4.
Hum Mol Genet ; 31(3): 347-361, 2022 02 03.
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 (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.


Assuntos
Estudo de Associação Genômica Ampla , Medicina de Precisão , Plaquetas , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Estados Unidos
5.
Genet Epidemiol ; 46(1): 3-16, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34779012

RESUMO

Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.


Assuntos
Estudo de Associação Genômica Ampla , Transcriptoma , Células Sanguíneas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
7.
Nature ; 599(7886): 628-634, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34662886

RESUMO

A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study2. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10-11. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene-trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.


Assuntos
Bancos de Espécimes Biológicos , Bases de Dados Genéticas , Exoma/genética , Sequenciamento Completo do Exoma , África/etnologia , Ásia/etnologia , Asma/genética , Diabetes Mellitus/genética , Europa (Continente)/etnologia , Oftalmopatias/genética , Feminino , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Hepatopatias/genética , Masculino , Mutação , Neoplasias/genética , Característica Quantitativa Herdável , Reino Unido
8.
J Am Heart Assoc ; 10(19): e018513, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34581201

RESUMO

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.


Assuntos
Insuficiência Cardíaca , Síndrome do QT Longo , Isquemia Miocárdica , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Estudos de Coortes , Morte Súbita Cardíaca/epidemiologia , Atenção à Saúde , Feminino , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/epidemiologia , Masculino , Pessoa de Meia-Idade
9.
Nat Commun ; 12(1): 4877, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385434

RESUMO

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Glaucoma/fisiopatologia , Pressão Intraocular/fisiologia , Malha Trabecular/fisiopatologia , Fatores de Transcrição/metabolismo , Animais , Humor Aquoso/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Glaucoma/genética , Glaucoma/metabolismo , Células HEK293 , Humanos , Pressão Intraocular/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA-Seq/métodos , Malha Trabecular/metabolismo , Fatores de Transcrição/genética
10.
Clin Exp Allergy ; 51(11): 1410-1420, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34459047

RESUMO

BACKGROUND: Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes. OBJECTIVE: We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations. METHODS: We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire. RESULTS: For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)). CONCLUSION: Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.


Assuntos
Asma , Predisposição Genética para Doença , Asma/epidemiologia , Asma/genética , Feminino , Humanos , Masculino , Fatores de Risco
11.
Genes (Basel) ; 12(7)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34356065

RESUMO

BACKGROUND: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. METHODS: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. RESULTS: Our results revealed 24 suggestive signals (p < 1 × 10-4) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. CONCLUSIONS: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.


Assuntos
Afro-Americanos/genética , Células Sanguíneas/patologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Transcriptoma , Células Sanguíneas/metabolismo , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , /genética
12.
Commun Biol ; 4(1): 864, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294844

RESUMO

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Transtornos de Enxaqueca/genética , Adulto , Afro-Americanos/genética , Idoso , Americanos Asiáticos/genética , Mapeamento Cromossômico , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etnologia , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , /genética
13.
Front Immunol ; 12: 684326, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177931

RESUMO

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.


Assuntos
Alelos , Variações do Número de Cópias de DNA , Psoríase/genética , Receptores KIR2DL2/genética , Estudos de Casos e Controles , Europa (Continente) , Predisposição Genética para Doença , Antígenos HLA-A , Antígenos HLA-B , Humanos , Modelos Logísticos , América do Norte , Polimorfismo de Nucleotídeo Único
14.
Nat Commun ; 12(1): 3595, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127677

RESUMO

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.


Assuntos
Catarata/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Envelhecimento , Animais , Caspase 7/genética , Estudos de Coortes , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Cristalino , Modelos Logísticos , Camundongos , Camundongos Knockout , Epidemiologia Molecular , Ribonucleoproteínas/genética , Fatores Sexuais
15.
PLoS Genet ; 17(5): e1009497, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33979322

RESUMO

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.


Assuntos
Bancos de Espécimes Biológicos , Variação Genética , Fenótipo , Retina/metabolismo , Tomografia de Coerência Óptica , Feminino , Genótipo , Glaucoma/genética , Glaucoma/patologia , Cor de Cabelo/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Controle de Qualidade , Retina/patologia , Reino Unido , Transtornos da Visão , Acuidade Visual/genética
16.
Am J Epidemiol ; 190(10): 2163-2171, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843952

RESUMO

Weight loss or lower body mass index (BMI) could be an early symptom of Alzheimer disease (AD), but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we leveraged variation in genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. We studied UK Biobank participants enrolled in 2006-2010, who were without dementia, aged 39-73, with European genetic ancestry. BMI was calculated with measured height/weight (weight (kg)/height (m)2). An AD genetic risk score (AD-GRS) was calculated based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI, stratified by decade, and calculated the age of divergence in BMI trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39- to 49-year-olds (ß = 0.00, 95% confidence interval (CI): -0.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (ß = -0.03, 95% CI: -0.06, -0.01) and 60- to 73-year-olds (ß = -0.09, 95% CI:-0.12, -0.07). Model-based BMI age curves for high versus low AD-GRS began to diverge after age 47 years. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes might begin to reduce BMI decades prior to dementia diagnosis.


Assuntos
Doença de Alzheimer/genética , Índice de Massa Corporal , Predisposição Genética para Doença/genética , Perda de Peso/genética , Adulto , Idoso , Doença de Alzheimer/epidemiologia , Causalidade , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Modelos Lineares , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido , /genética
17.
Transl Psychiatry ; 11(1): 120, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33633108

RESUMO

Cigarette smoking contributes to numerous diseases and is one of the leading causes of death in the United States. Smoking behaviors vary widely across race/ethnicity, but it is not clear why. Here, we examine the contribution of genetic ancestry to variation in two smoking-related traits in 43,485 individuals from four race/ethnicity groups (non-Hispanic white, Hispanic/Latino, East Asian, and African American) from a single U.S. healthcare plan. Smoking prevalence was the lowest among East Asians (22.7%) and the highest among non-Hispanic whites (38.5%). We observed significant associations between genetic ancestry and smoking-related traits. Within East Asians, we observed higher smoking prevalence with greater European (versus Asian) ancestry (P = 9.95 × 10-12). Within Hispanic/Latinos, higher cigarettes per day (CPD) was associated with greater European ancestry (P = 3.34 × 10-25). Within non-Hispanic whites, the lowest number of CPD was observed for individuals of southeastern European ancestry (P = 9.06 × 10-5). These associations remained after considering known smoking-associated loci, education, socioeconomic factors, and marital status. Our findings support the role of genetic ancestry and socioeconomic factors in cigarette smoking behaviors in non-Hispanic whites, Hispanic/Latinos, and East Asians.


Assuntos
Fumar Cigarros , Afro-Americanos/genética , /genética , Humanos , Prevalência , Estados Unidos/epidemiologia , /genética
18.
Nat Commun ; 12(1): 1258, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627673

RESUMO

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Glaucoma de Ângulo Aberto/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
19.
Nat Commun ; 12(1): 970, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579919

RESUMO

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.


Assuntos
Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Epidemiologia Molecular , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
20.
Cancer Res ; 81(7): 1695-1703, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33293427

RESUMO

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.


Assuntos
Herança Multifatorial , Neoplasias da Próstata , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética
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