RESUMO
Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. Unfortunately, existing methods for identifying AIMs require knowing ancestry labels for a subset of the sample. This supervised learning approach creates a chicken and the egg scenario. In this paper, we present an unsupervised, scalable framework that seamlessly carries out AIM selection and likelihood-based estimation of admixture proportions. Our simulated and real data examples show that this approach is scalable to modern biobank datasets. OpenADMIXTURE, our Julia implementation of the method, is open source and available for free.
Assuntos
Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Humanos , Estudo de Associação Genômica Ampla/métodos , Funções Verossimilhança , Grupos Populacionais , Software , Genética PopulacionalRESUMO
MOTIVATION: Current methods for genotype imputation and phasing exploit the volume of data in haplotype reference panels and rely on hidden Markov models (HMMs). Existing programs all have essentially the same imputation accuracy, are computationally intensive and generally require prephasing the typed markers. RESULTS: We introduce a novel data-mining method for genotype imputation and phasing that substitutes highly efficient linear algebra routines for HMM calculations. This strategy, embodied in our Julia program MendelImpute.jl, avoids explicit assumptions about recombination and population structure while delivering similar prediction accuracy, better memory usage and an order of magnitude or better run-times compared to the fastest competing method. MendelImpute operates on both dosage data and unphased genotype data and simultaneously imputes missing genotypes and phase at both the typed and untyped SNPs (single nucleotide polymorphisms). Finally, MendelImpute naturally extends to global and local ancestry estimation and lends itself to new strategies for data compression and hence faster data transport and sharing. AVAILABILITY AND IMPLEMENTATION: Software, documentation and scripts to reproduce our results are available from https://github.com/OpenMendel/MendelImpute.jl. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Compressão de Dados , Software , Genótipo , Haplótipos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Statistical geneticists employ simulation to estimate the power of proposed studies, test new analysis tools, and evaluate properties of causal models. Although there are existing trait simulators, there is ample room for modernization. For example, most phenotype simulators are limited to Gaussian traits or traits transformable to normality, while ignoring qualitative traits and realistic, non-normal trait distributions. Also, modern computer languages, such as Julia, that accommodate parallelization and cloud-based computing are now mainstream but rarely used in older applications. To meet the challenges of contemporary big studies, it is important for geneticists to adopt new computational tools. RESULTS: We present TraitSimulation, an open-source Julia package that makes it trivial to quickly simulate phenotypes under a variety of genetic architectures. This package is integrated into our OpenMendel suite for easy downstream analyses. Julia was purpose-built for scientific programming and provides tremendous speed and memory efficiency, easy access to multi-CPU and GPU hardware, and to distributed and cloud-based parallelization. TraitSimulation is designed to encourage flexible trait simulation, including via the standard devices of applied statistics, generalized linear models (GLMs) and generalized linear mixed models (GLMMs). TraitSimulation also accommodates many study designs: unrelateds, sibships, pedigrees, or a mixture of all three. (Of course, for data with pedigrees or cryptic relationships, the simulation process must include the genetic dependencies among the individuals.) We consider an assortment of trait models and study designs to illustrate integrated simulation and analysis pipelines. Step-by-step instructions for these analyses are available in our electronic Jupyter notebooks on Github. These interactive notebooks are ideal for reproducible research. CONCLUSION: The TraitSimulation package has three main advantages. (1) It leverages the computational efficiency and ease of use of Julia to provide extremely fast, straightforward simulation of even the most complex genetic models, including GLMs and GLMMs. (2) It can be operated entirely within, but is not limited to, the integrated analysis pipeline of OpenMendel. And finally (3), by allowing a wider range of more realistic phenotype models, TraitSimulation brings power calculations and diagnostic tools closer to what investigators might see in real-world analyses.
Assuntos
Computação em Nuvem , Testes Genéticos , Idoso , Simulação por Computador , Humanos , Linhagem , FenótipoRESUMO
Statistical methods for genome-wide association studies (GWAS) continue to improve. However, the increasing volume and variety of genetic and genomic data make computational speed and ease of data manipulation mandatory in future software. In our view, a collaborative effort of statistical geneticists is required to develop open source software targeted to genetic epidemiology. Our attempt to meet this need is called the OPENMENDEL project (https://openmendel.github.io). It aims to (1) enable interactive and reproducible analyses with informative intermediate results, (2) scale to big data analytics, (3) embrace parallel and distributed computing, (4) adapt to rapid hardware evolution, (5) allow cloud computing, (6) allow integration of varied genetic data types, and (7) foster easy communication between clinicians, geneticists, statisticians, and computer scientists. This article reviews and makes recommendations to the genetic epidemiology community in the context of the OPENMENDEL project.
Assuntos
Biologia Computacional/métodos , Genoma Humano , Estudo de Associação Genômica Ampla , Modelos Estatísticos , Linguagens de Programação , Algoritmos , Humanos , Polimorfismo de Nucleotídeo Único , SoftwareRESUMO
Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel.
Assuntos
Ligação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Humanos , Modelos Genéticos , Modelos Estatísticos , SoftwareRESUMO
PURPOSE: Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. METHODS: With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP-glucose variations. We used regression analysis plus stratification and graphic approaches. RESULTS: Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants' effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). CONCLUSIONS: Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism-relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women.
Assuntos
Variação Genética , Glucose/metabolismo , Obesidade/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Glicemia/análise , Índice de Massa Corporal , Diacilglicerol Quinase/genética , Dieta Hiperlipídica , Exercício Físico , Feminino , Genótipo , Quinases do Centro Germinativo , Humanos , Insulina/sangue , Resistência à Insulina , Estilo de Vida , Pessoa de Meia-Idade , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Proteínas Serina-Treonina Quinases/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genéticaRESUMO
BACKGROUND: Impaired glucose metabolism-related genetic variants and traits likely interact with obesity and related lifestyle factors, influencing postmenopausal breast and colorectal cancer (CRC), but their interconnected pathways are not fully understood. By stratifying via obesity and lifestyles, we partitioned the total effect of glucose metabolism genetic variants on cancer risk into two putative mechanisms: 1) indirect (risk-associated glucose metabolism genetic variants mediated by glucose metabolism traits) and 2) direct (risk-associated glucose metabolism genetic variants through pathways other than glucose metabolism traits) effects. METHOD: Using 16 single-nucleotide polymorphisms (SNPs) associated with glucose metabolism and data from 5379 postmenopausal women in the Women's Health Initiative Harmonized and Imputed Genome-Wide Association Studies, we retrospectively assessed the indirect and direct effects of glucose metabolism-traits (fasting glucose, insulin, and homeostatic model assessment-insulin resistance [HOMA-IR]) using two quantitative tests. RESULTS: Several SNPs were associated with breast cancer and CRC risk, and these SNP-cancer associations differed between non-obese and obese women. In both strata, the direct effect of cancer risk associated with the SNP accounted for the majority of the total effect for most SNPs, with roughly 10% of cancer risk due to the SNP that was from an indirect effect mediated by glucose metabolism traits. No apparent differences in the indirect (glucose metabolism-mediated) effects were seen between non-obese and obese women. It is notable that among obese women, 50% of cancer risk was mediated via glucose metabolism trait, owing to two SNPs: in breast cancer, in relation to GCKR through glucose, and in CRC, in relation to DGKB/TMEM195 through HOMA-IR. CONCLUSIONS: Our findings suggest that glucose metabolism genetic variants interact with obesity, resulting in altered cancer risk through pathways other than those mediated by glucose metabolism traits.
Assuntos
Glicemia/metabolismo , Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Obesidade/genética , Pós-Menopausa/genética , Idoso , Glicemia/genética , Neoplasias da Mama/epidemiologia , Neoplasias Colorretais/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Insulina/metabolismo , Resistência à Insulina , Pessoa de Meia-Idade , Obesidade/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
BACKGROUND/AIMS: Maternal and offspring cell contact at the site of placentation presents a plausible setting for maternal-fetal genotype (MFG) interactions affecting fetal growth. We test hypotheses regarding killer cell immunoglobulin-like receptor (KIR) and HLA-C MFG effects on human birth weight by extending the quantitative MFG (QMFG) test. METHODS: Until recently, association testing for MFG interactions had limited applications. To improve the ability to test for these interactions, we developed the extended QMFG test, a linear mixed-effect model that can use multi-locus genotype data from families. RESULTS: We demonstrate the extended QMFG test's statistical properties. We also show that if an offspring-only model is fit when MFG effects exist, associations can be missed or misattributed. Furthermore, imprecisely modeling the effects of both KIR and HLA-C could result in a failure to replicate if these loci's allele frequencies differ among populations. To further illustrate the extended QMFG test's advantages, we apply the extended QMFG test to a UK cohort study and the Norwegian Mother and Child Cohort (MoBa) study. CONCLUSION: We find a significant KIR-HLA-C interaction effect on birth weight. More generally, the QMFG test can detect genetic associations that may be missed by standard genome-wide association studies for quantitative traits.
Assuntos
Peso ao Nascer/genética , Estudo de Associação Genômica Ampla/métodos , Antígenos HLA-C/genética , Receptores KIR/genética , Estudos de Coortes , Feminino , Desenvolvimento Fetal/genética , Genótipo , Humanos , GravidezRESUMO
Maternal-offspring gene interactions, aka maternal-fetal genotype (MFG) incompatibilities, are neglected in complex diseases and quantitative trait studies. They are implicated in birth to adult onset diseases but there are limited ways to investigate their influence on quantitative traits. We present the quantitative-MFG (QMFG) test, a linear mixed model where maternal and offspring genotypes are fixed effects and residual correlations between family members are random effects. The QMFG handles families of any size, common or general scenarios of MFG incompatibility, and additional covariates. We develop likelihood ratio tests (LRTs) and rapid score tests and show they provide correct inference. In addition, the LRT's alternative model provides unbiased parameter estimates. We show that testing the association of SNPs by fitting a standard model, which only considers the offspring genotypes, has very low power or can lead to incorrect conclusions. We also show that offspring genetic effects are missed if the MFG modeling assumptions are too restrictive. With genome-wide association study data from the San Antonio Family Heart Study, we demonstrate that the QMFG score test is an effective and rapid screening tool. The QMFG test therefore has important potential to identify pathways of complex diseases for which the genetic etiology remains to be discovered.
Assuntos
Predisposição Genética para Doença , Genótipo , Modelos Lineares , Modelos Genéticos , Simulação por Computador , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Funções Verossimilhança , Linhagem , Polimorfismo de Nucleotídeo Único , Gravidez , Característica Quantitativa HerdávelRESUMO
Ultraconserved elements (UCEs) have become popular markers in phylogenomic studies because of their cost effectiveness and their potential to resolve problematic phylogenetic relationships. Although UCE datasets typically contain a much larger number of loci and sites than more traditional datasets of PCR-amplified, single-copy, protein coding genes, a fraction of UCE sites are expected to be part of a nearly invariant core, and the relative performance of UCE datasets versus protein coding gene datasets is poorly understood. Here we use phylogenetic informativeness (PI) to compare the resolving power of multi-locus and UCE datasets in a sample of percomorph fishes with sequenced genomes (genome-enabled). We compare three data sets: UCE core regions, flanking sequence adjacent to the UCE core and a set of ten protein coding genes commonly used in fish systematics. We found the net informativeness of UCE core and flank regions to be roughly ten-fold and 100-fold more informative than that of the protein coding genes. On a per locus basis UCEs and protein coding genes exhibited similar levels of phylogenetic informativeness. Our results suggest that UCEs offer enormous potential for resolving relationships across the percomorph tree of life.
Assuntos
Sequência Conservada/genética , Peixes/genética , Genoma , Filogenia , Animais , Intervalos de Confiança , Bases de Dados Genéticas , Loci Gênicos , Marcadores Genéticos , Modelos Lineares , Nucleotídeos/genética , Fases de Leitura Aberta/genética , Reprodutibilidade dos TestesRESUMO
UNLABELLED: Mendel is one of the few statistical genetics packages that provide a full spectrum of gene mapping methods, ranging from parametric linkage in large pedigrees to genome-wide association with rare variants. Our latest additions to Mendel anticipate and respond to the needs of the genetics community. Compared with earlier versions, Mendel is faster and easier to use and has a wider range of applications. Supported platforms include Linux, MacOS and Windows. AVAILABILITY: Free from www.genetics.ucla.edu/software/mendel.
Assuntos
Mapeamento Cromossômico/métodos , Software , Interpretação Estatística de Dados , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , LinhagemRESUMO
MOTIVATION: In modern sequencing studies, one can improve the confidence of genotype calls by phasing haplotypes using information from an external reference panel of fully typed unrelated individuals. However, the computational demands are so high that they prohibit researchers with limited computational resources from haplotyping large-scale sequence data. RESULTS: Our graphics processing unit based software delivers haplotyping and imputation accuracies comparable to competing programs at a fraction of the computational cost and peak memory demand. AVAILABILITY: Mendel-GPU, our OpenCL software, runs on Linux platforms and is portable across AMD and nVidia GPUs. Users can download both code and documentation at http://code.google.com/p/mendel-gpu/. CONTACT: gary.k.chen@usc.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Algoritmos , Genótipo , Software , Genoma Humano , Estudo de Associação Genômica Ampla , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Insulin resistance (IR) is a well-established risk factor for breast cancer (BC) development in African American (AA) postmenopausal women. While obesity and IR are more prevalent in AA than in white women, they are under-represented in genome-wide studies for systemic regulation of IR. By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in our data, we tested 4689 AA women in a Random Survival Forest framework. With 37 BC-associated lifestyle factors, we conducted a gene-environment interaction analysis to estimate risk prediction for BC with the most influential genetic and behavioral factors and evaluated their combined and joint effects on BC risk. By accounting for variations of individual SNPs in BC in the prediction model, we detected four fasting glucose-associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and three lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyle with smoking revealed a synergistic effect on the increased risk of BC, particularly estrogen/progesterone positive (ER/PR+) BC, in a gene-lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with prolonged exposure to cigarette smoking and female hormones. The top genome-wide association-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR+ BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.
Assuntos
Neoplasias da Mama , Resistência à Insulina , Feminino , Humanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Negro ou Afro-Americano/genética , Fumar , Fatores de Risco , Resistência à Insulina/genética , Glucose , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The need to collect accurate and complete pedigree information has been a drawback of family-based linkage and association studies. Even in case-control studies, investigators should be aware of, and condition on, familial relationships. In single nucleotide polymorphism (SNP) genome scans, relatedness can be directly inferred from the genetic data rather than determined through interviews. Various methods of estimating relatedness have previously been implemented, most notably in PLINK. We present new fast and accurate algorithms for estimating global and local kinship coefficients from dense SNP genotypes. These algorithms require only a single pass through the SNP genotype data. We also show that these estimates can be used to cluster individuals into pedigrees. With these estimates in hand, quantitative trait locus linkage analysis proceeds via traditional variance components methods without any prior relationship information. We demonstrate the success of our algorithms on simulated and real data sets. Our procedures make linkage analysis as easy as a typical genomewide association study.
Assuntos
Ligação Genética , Linhagem , Algoritmos , Alelos , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Locos de Características QuantitativasRESUMO
Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8-16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Trissomia/genética , Humanos , Lactente , Metanálise como Assunto , FenótipoRESUMO
OBJECTIVES: Non-parametric linkage analysis (NPL) exploits marker allele sharing among affected relatives to map genes influencing complex traits. Computational barriers force approximate analysis on large pedigrees and the adoption of a questionable perfect data assumption (PDA) in assigning p values. To improve NPL significance testing on large pedigrees, we examine the adverse consequences of missing data and PDA. We also introduce a novel statistic, Q-NPL, appropriate for NPL analysis of quantitative traits. METHODS: Using simulated and real data sets with qualitative traits, we compare NPL analysis results for four testing procedures and various degrees of missing data. The simulated data sets vary from all nuclear families, to all large pedigrees, to a mix of pedigrees of different sizes. We implemented the Kong and Cox linear adjustment of p values in the software packages Mendel and SimWalk. We perform similar analysis with Q-NPL on quantitative traits of various heritabilities. RESULTS: The Kong and Cox extension for significance testing is robust to realistic missing data patterns, greatly improves p values in approximate analyses, and works equally well for qualitative and quantitative traits and small and large pedigrees. The Q-NPL statistic is robust to missing data and shows good power to detect linkage for quantitative traits with a wide spectrum of heritabilities. CONCLUSIONS: The Kong and Cox extension should be a standard tool for calculating NPL p values. It allows the combination of exact and estimated analyses into a single significance score. Q-NPL should be a standard statistic for NPL analysis of quantitative traits. The new statistics are implemented in Mendel and SimWalk.
Assuntos
Mapeamento Cromossômico/métodos , Ligação Genética , Humanos , Linhagem , Locos de Características Quantitativas , Estatísticas não ParamétricasRESUMO
BACKGROUND AND METHODS: Association studies using unrelated individuals cannot detect intergenerational genetic effects contributing to disease. To detect these effects, we improve the extended maternal-fetal genotype (EMFG) incompatibility test to estimate any combination of maternal effects, offspring effects, and their interactions at polymorphic loci or multiple SNPs, using any size pedigrees. We explore the advantages of using extended pedigrees rather than nuclear families. We apply our methods to schizophrenia pedigrees to investigate whether the previously associated mother-daughter HLA-B matching is a genuine risk or the result of bias. RESULTS: Simulations demonstrate that using the EMFG test with extended pedigrees increases power and precision, while partitioning extended pedigrees into nuclear families can underestimate intergenerational effects. Application to actual data demonstrates that mother-daughter HLA-B matching remains a schizophrenia risk factor. Furthermore, ascertainment and mate selection biases cannot by themselves explain the observed HLA-B matching and schizophrenia association. CONCLUSIONS: Our results demonstrate the power of the EMFG test to examine intergenerational genetic effects, highlight the importance of pedigree rather than case/control or case-mother/control-mother designs, illustrate that pedigrees provide a means to examine alternative, non-causal mechanisms, and they strongly support the hypothesis that HLA-B matching is causally involved in the etiology of schizophrenia in females.
Assuntos
Predisposição Genética para Doença , Antígenos HLA-B/genética , Hereditariedade/genética , Teste de Histocompatibilidade/métodos , Esquizofrenia/genética , Alelos , Simulação por Computador , Bases de Dados Genéticas , Características da Família , Feminino , Antígenos HLA-B/imunologia , Histocompatibilidade Materno-Fetal/genética , Humanos , Funções Verossimilhança , Masculino , Modelos Genéticos , Linhagem , Fatores de Risco , Esquizofrenia/imunologiaRESUMO
Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.
Assuntos
HDL-Colesterol/biossíntese , Oxirredutases/genética , Oxirredutases/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia , Adolescente , Adulto , Idoso , Alelos , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Finlândia , Genética Populacional , Humanos , Masculino , México , Pessoa de Meia-Idade , Polimorfismo Genético , Oxidorredutase com Domínios WWRESUMO
As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene-gene interaction networks enriched by those topmost pathways, we identified KDs-both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)-in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Redes Reguladoras de Genes , Genômica , Inflamação/genética , Transdução de Sinais/genética , Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Feminino , Humanos , Interleucina-6/metabolismo , Fígado/metabolismo , Especificidade de Órgãos/genética , Fenótipo , Mapas de Interação de Proteínas/genéticaRESUMO
BACKGROUND: Disparities in cancer genomic science exist among racial/ethnic minorities. Particularly, African American (AA) and Hispanic/Latino American (HA) women, the 2 largest minorities, are underrepresented in genetic/genome-wide studies for cancers and their risk factors. We conducted on AA and HA postmenopausal women a genomic study for insulin resistance (IR), the main biologic mechanism underlying colorectal cancer (CRC) carcinogenesis owing to obesity. METHODS: With 780 genome-wide IR-specific single-nucleotide polymorphisms (SNPs) among 4,692 AA and 1,986 HA women, we constructed a CRC-risk prediction model. Along with these SNPs, we incorporated CRC-associated lifestyles in the model of each group and detected the topmost influential genetic and lifestyle factors. Further, we estimated the attributable risk of the topmost risk factors shared by the groups to explore potential factors that differentiate CRC risk between these groups. RESULTS: In both groups, we detected IR-SNPs in PCSK1 (in AA) and IFT172, GCKR, and NRBP1 (in HA) and risk lifestyles, including long lifetime exposures to cigarette smoking and endogenous female hormones and daily intake of polyunsaturated fatty acids (PFA), as the topmost predictive variables for CRC risk. Combinations of those top genetic- and lifestyle-markers synergistically increased CRC risk. Of those risk factors, dietary PFA intake and long lifetime exposure to female hormones may play a key role in mediating racial disparity of CRC incidence between AA and HA women. CONCLUSIONS: Our results may improve CRC risk prediction performance in those medically/scientifically underrepresented groups and lead to the development of genetically informed interventions for cancer prevention and therapeutic effort, thus contributing to reduced cancer disparities in those minority subpopulations.