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1.
Proc Natl Acad Sci U S A ; 117(5): 2560-2569, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964835

RESUMO

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h 2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.

2.
Am J Hum Genet ; 105(5): 883-893, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587867

RESUMO

The two primary methods for estimating the genome-wide mutation rate have been counting de novo mutations in parent-offspring trios and comparing sequence data between closely related species. With parent-offspring trio analysis it is difficult to control for genotype error, and resolution is limited because each trio provides information from only two meioses. Inter-species comparison is difficult to calibrate due to uncertainty in the number of meioses separating species, and it can be biased by selection and by changing mutation rates over time. An alternative class of approaches for estimating mutation rates that avoids these limitations is based on identity by descent (IBD) segments that arise from common ancestry within the past few thousand years. Existing IBD-based methods are limited to highly inbred samples, or lack robustness to genotype error and error in the estimated demographic history. We present an IBD-based method that uses sharing of IBD segments among sets of three individuals to estimate the mutation rate. Our method is applicable to accurately phased genotype data, such as parent-offspring trio data phased using Mendelian rules of inheritance. Unlike standard parent-offspring analysis, our method utilizes distant relationships and is robust to genotype error. We apply our method to data from 1,307 European-ancestry individuals in the Framingham Heart Study sequenced by the NHLBI TOPMed project. We obtain an estimate of 1.29 × 10-8 mutations per base pair per meiosis with a 95% confidence interval of [1.02 × 10-8, 1.56 × 10-8].

3.
Am J Hum Genet ; 104(3): 454-465, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773276

RESUMO

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10-5 and 4.5 × 10-6 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.


Assuntos
Afro-Americanos/genética , Biologia Computacional/métodos , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional , Genoma Humano , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Idoso , Mapeamento Cromossômico , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Pós-Menopausa
4.
Hum Mol Genet ; 28(4): 675-687, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30403821

RESUMO

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.


Assuntos
Ferroquelatase/genética , Estudo de Associação Genômica Ampla , Apneia Obstrutiva do Sono/genética , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico por imagem , Apneia Obstrutiva do Sono/fisiopatologia
5.
Am J Hum Genet ; 103(3): 338-348, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30100085

RESUMO

Genotype imputation is commonly performed in genome-wide association studies because it greatly increases the number of markers that can be tested for association with a trait. In general, one should perform genotype imputation using the largest reference panel that is available because the number of accurately imputed variants increases with reference panel size. However, one impediment to using larger reference panels is the increased computational cost of imputation. We present a new genotype imputation method, Beagle 5.0, which greatly reduces the computational cost of imputation from large reference panels. We compare Beagle 5.0 with Beagle 4.1, Impute4, Minimac3, and Minimac4 using 1000 Genomes Project data, Haplotype Reference Consortium data, and simulated data for 10k, 100k, 1M, and 10M reference samples. All methods produce nearly identical accuracy, but Beagle 5.0 has the lowest computation time and the best scaling of computation time with increasing reference panel size. For 10k, 100k, 1M, and 10M reference samples and 1,000 phased target samples, Beagle 5.0's computation time is 3× (10k), 12× (100k), 43× (1M), and 533× (10M) faster than the fastest alternative method. Cost data from the Amazon Elastic Compute Cloud show that Beagle 5.0 can perform genome-wide imputation from 10M reference samples into 1,000 phased target samples at a cost of less than one US cent per sample.


Assuntos
Genoma Humano/genética , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Software
6.
PLoS Genet ; 14(5): e1007385, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29795556

RESUMO

Populations change in size over time due to factors such as population growth, migration, bottleneck events, natural disasters, and disease. The historical effective size of a population affects the power and resolution of genetic association studies. For admixed populations, it is not only the overall effective population size that is of interest, but also the effective sizes of the component ancestral populations. We use identity by descent and local ancestry inferred from genome-wide genetic data to estimate overall and ancestry-specific effective population size during the past hundred generations for nine admixed American populations from the Hispanic Community Health Study/Study of Latinos, and for African-American and European-American populations from two US cities. In these populations, the estimated pre-admixture effective sizes of the ancestral populations vary by sampled population, suggesting that the ancestors of different sampled populations were drawn from different sub-populations. In addition, we estimate that overall effective population sizes dropped substantially in the generations immediately after the commencement of European and African immigration, reaching a minimum around 12 generations ago, but rebounded within a small number of generations afterwards. Of the populations that we considered, the population of individuals originating from Puerto Rico has the smallest bottleneck size of one thousand, while the Pittsburgh African-American population has the largest bottleneck size of two hundred thousand.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano/genética , Hispano-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Américas , Simulação por Computador , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Estudos de Associação Genética/métodos , Genética Populacional/métodos , Haplótipos , Hispano-Americanos/estatística & dados numéricos , Humanos , Densidade Demográfica , Estados Unidos
7.
Cell ; 173(1): 53-61.e9, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29551270

RESUMO

Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. VIDEO ABSTRACT.


Assuntos
Genoma Humano , Animais , Grupo com Ancestrais do Continente Asiático/genética , Humanos , Homem de Neandertal/genética , Seleção Genética , Sequenciamento Completo do Exoma
8.
Bioinformatics ; 34(16): 2854-2855, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29590339

RESUMO

Summary: We present POPdemog, an R package which converts coalescent simulation program input parameters into a visual representation of the demographic model. This package is useful for preparing figures, for checking that demographic simulation parameters have been correctly specified, and for understanding demographic models that other researchers have used to simulate genetic data. The POPdemog package supports the ms, msa, msHot, MaCS, msprime, scrm and Cosi2 programs, and includes options for customizing the output figures. Availability and implementation: The POPdemog package and its tutorial can be freely downloaded from https://github.com/YingZhou001/POPdemog. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Demografia , Genética Populacional
9.
PLoS One ; 12(11): e0188400, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29155883

RESUMO

Admixture mapping can be used to detect genetic association regions in admixed populations, such as Hispanics/Latinos, by estimating associations between local ancestry allele counts and the trait of interest. We performed admixture mapping of the blood pressure traits systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), and pulse pressure (PP), in a dataset of 12,116 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanics/Latinos have three predominant ancestral populations (European, African, and Amerindian), for each of which we separately tested local ancestry intervals across the genome. We identified four regions that were significantly associated with a blood pressure trait at the genome-wide admixture mapping level. A 6p21.31 Amerindian ancestry association region has multiple known associations, but none explained the admixture mapping signal. We identified variants that completely explained this signal. One of these variants had p-values of 0.02 (MAP) and 0.04 (SBP) in replication testing in Pima Indians. A 11q13.4 Amerindian ancestry association region spans a variant that was previously reported (p-value = 0.001) in a targeted association study of Blood Pressure (BP) traits and variants in the vitamin D pathway. There was no replication evidence supporting an association in the identified 17q25.3 Amerindian ancestry association region. For a region on 6p12.3, associated with African ancestry, we did not identify any candidate variants driving the association. It may be driven by rare variants. Whole genome sequence data may be necessary to fine map these association signals, which may contribute to disparities in BP traits between diverse populations.


Assuntos
Pressão Sanguínea/genética , Mapeamento Cromossômico , Genoma Humano , Hipertensão/etnologia , Hipertensão/genética , Característica Quantitativa Herdável , Grupo com Ancestrais do Continente Africano , Diástole , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos , Humanos , Hipertensão/fisiopatologia , Índios Norte-Americanos , Estudos Longitudinais , Masculino , Sístole
10.
Heart Rhythm ; 14(11): 1675-1684, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28610988

RESUMO

BACKGROUND: Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. OBJECTIVE: The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). METHODS: We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10-8) or suggestive (P <10-6) significance thresholds. RESULTS: Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. CONCLUSION: This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.


Assuntos
Afro-Americanos , Arritmias Cardíacas/genética , Sistema Nervoso Autônomo/fisiopatologia , Estudo de Associação Genômica Ampla/métodos , Frequência Cardíaca/genética , Hispano-Americanos , Polimorfismo de Nucleotídeo Único , Arritmias Cardíacas/etnologia , Eletrocardiografia , Genótipo , Humanos , Fenótipo , Estados Unidos/epidemiologia
11.
PLoS Genet ; 13(4): e1006760, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28453575

RESUMO

Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.


Assuntos
Proteínas de Homeodomínio/genética , Complexo de Endopeptidases do Proteassoma/genética , RNA Longo não Codificante/genética , Membro 2 da Família 12 de Carreador de Soluto/genética , Proteínas Supressoras de Tumor/genética , alfa-Globinas/genética , Contagem de Eritrócitos , Eritrócitos , Feminino , Estudo de Associação Genômica Ampla , Hemoglobinas/genética , Hispano-Americanos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Globinas beta/genética
12.
Hum Mol Genet ; 26(6): 1193-1204, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28158719

RESUMO

Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, basophils) differ by ethnicity. The genetic factors underlying basal WBC traits in Hispanics/Latinos are unknown. We performed a genome-wide association study of total WBC and differential counts in a large, ethnically diverse US population sample of Hispanics/Latinos ascertained by the Hispanic Community Health Study and Study of Latinos (HCHS/SOL). We demonstrate that several previously known WBC-associated genetic loci (e.g. the African Duffy antigen receptor for chemokines null variant for neutrophil count) are generalizable to WBC traits in Hispanics/Latinos. We identified and replicated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) associated with monocyte count. The common FLT3 variant rs76428106 has a large allele frequency differential between African and non-African populations. We also identified several novel genetic loci involving or regulating hematopoietic transcription factors (CEBPE-SLC7A7, CEBPA and CRBN-TRNT1) associated with basophil count. The minor allele of the CEBPE variant associated with lower basophil count has been previously associated with Amerindian ancestry and higher risk of acute lymphoblastic leukemia in Hispanics. Together, these data suggest that germline genetic variation affecting transcriptional and signaling pathways that underlie WBC development and lineage specification can contribute to inter-individual as well as ethnic differences in peripheral blood cell counts (normal hematopoiesis) in addition to susceptibility to leukemia (malignant hematopoiesis).


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Estudo de Associação Genômica Ampla , Contagem de Leucócitos , Tirosina Quinase 3 Semelhante a fms/genética , Afro-Americanos/genética , Basófilos/citologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Hispano-Americanos/genética , Humanos , Linfócitos/citologia , Masculino , Monócitos/citologia , Neutrófilos/citologia , Estados Unidos/epidemiologia
13.
Am J Hum Genet ; 99(5): 1106-1116, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27745837

RESUMO

Identifying and characterizing genomic regions that are shared identical by descent (IBD) among individuals can yield insight into population history, facilitate the identification of adaptively evolving loci, and be an important tool in disease gene mapping. Although increasingly large collections of exome sequences have been generated, it is challenging to detect IBD segments in exomes, precluding many potentially informative downstream analyses. Here, we describe an approach, ExIBD, to robustly detect IBD segments in exome-sequencing data, rigorously evaluate its performance, and apply this method to high-coverage exomes from 6,515 European and African Americans. Furthermore, we show how IBD networks, constructed from patterns of pairwise IBD between individuals, and principles from graph theory provide insight into recent population history and reveal cryptic population structure in European Americans. Our results enable IBD analyses to be performed on exome data, which will expand the scope of inferences that can be made from existing massively large exome-sequencing datasets.


Assuntos
Bases de Dados Genéticas , Exoma , Genética Populacional/métodos , Análise de Sequência de DNA , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Genômica , Técnicas de Genotipagem , Humanos , Modelos Biológicos , Polimorfismo de Nucleotídeo Único
14.
Bioinformatics ; 32(14): 2227-9, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27153656

RESUMO

UNLABELLED: In a genome-wide association study (GWAS) of an admixed population, such as Hispanic Americans, ancestry-specific allele frequencies can inform the design of a replication GWAS. We derive an EM algorithm to estimate ancestry-specific allele frequencies for a bi-allelic marker given genotypes and local ancestries on a 3-way admixed population, when the phase of each admixed individual's genotype relative to the pair of local ancestries is unknown. We call our algorithm Ancestry Specific Allele Frequency Estimation (ASAFE). We demonstrate that ASAFE has low error on simulated data. AVAILABILITY AND IMPLEMENTATION: The R source code for ASAFE is available for download at https://github.com/BiostatQian/ASAFE CONTACT: qszhang@uw.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Frequência do Gene , Genética Populacional/métodos , Algoritmos , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos
15.
G3 (Bethesda) ; 6(6): 1525-34, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27172203

RESUMO

We estimated local ancestry on the autosomes and X chromosome in a large US-based study of 12,793 Hispanic/Latino individuals using the RFMix method, and we compared different reference panels and approaches to local ancestry estimation on the X chromosome by means of Mendelian inconsistency rates as a proxy for accuracy. We developed a novel and straightforward approach to performing ancestry-specific PCA after finding artifactual behavior in the results from an existing approach. Using the ancestry-specific PCA, we found significant population structure within African, European, and Amerindian ancestries in the Hispanic/Latino individuals in our study. In the African ancestral component of the admixed individuals, individuals whose grandparents were from Central America clustered separately from individuals whose grandparents were from the Caribbean, and also from reference Yoruba and Mandenka West African individuals. In the European component, individuals whose grandparents were from Puerto Rico diverged partially from other background groups. In the Amerindian ancestral component, individuals clustered into multiple different groups depending on the grandparental country of origin. Therefore, local ancestry estimation provides further insight into the complex genetic structure of US Hispanic/Latino populations, which must be properly accounted for in genotype-phenotype association studies. It also provides a basis for admixture mapping and ancestry-specific allele frequency estimation, which are useful in the identification of risk factors for disease.


Assuntos
Genética Populacional , Hispano-Americanos/genética , Vigilância em Saúde Pública , Adolescente , Adulto , Idoso , Alelos , Feminino , Frequência do Gene , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Estados Unidos/etnologia , Adulto Jovem
16.
Am J Hum Genet ; 98(1): 116-26, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26748515

RESUMO

We present a genotype imputation method that scales to millions of reference samples. The imputation method, based on the Li and Stephens model and implemented in Beagle v.4.1, is parallelized and memory efficient, making it well suited to multi-core computer processors. It achieves fast, accurate, and memory-efficient genotype imputation by restricting the probability model to markers that are genotyped in the target samples and by performing linear interpolation to impute ungenotyped variants. We compare Beagle v.4.1 with Impute2 and Minimac3 by using 1000 Genomes Project data, UK10K Project data, and simulated data. All three methods have similar accuracy but different memory requirements and different computation times. When imputing 10 Mb of sequence data from 50,000 reference samples, Beagle's throughput was more than 100× greater than Impute2's throughput on our computer servers. When imputing 10 Mb of sequence data from 200,000 reference samples in VCF format, Minimac3 consumed 26× more memory per computational thread and 15× more CPU time than Beagle. We demonstrate that Beagle v.4.1 scales to much larger reference panels by performing imputation from a simulated reference panel having 5 million samples and a mean marker density of one marker per four base pairs.


Assuntos
Bases de Dados Genéticas , Genótipo , Padrões de Referência
17.
Am J Hum Genet ; 98(1): 165-84, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26748518

RESUMO

US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a "genetic-analysis group" variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.


Assuntos
Variação Genética , Hispano-Americanos/genética , Estudo de Associação Genômica Ampla , Humanos , Estados Unidos
18.
Am J Hum Genet ; 98(2): 229-42, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26805783

RESUMO

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10(-28)) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits.


Assuntos
Estudos de Associação Genética/métodos , Loci Gênicos , Hispano-Americanos/genética , Contagem de Plaquetas , Actinina/genética , Adolescente , Adulto , Idoso , Alelos , Frequência do Gene , Genótipo , Técnicas de Genotipagem , Humanos , Fatores de Transcrição MEF2/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de GABA-B/genética , Adulto Jovem
19.
Am J Hum Genet ; 97(3): 404-18, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26299365

RESUMO

Existing methods for estimating historical effective population size from genetic data have been unable to accurately estimate effective population size during the most recent past. We present a non-parametric method for accurately estimating recent effective population size by using inferred long segments of identity by descent (IBD). We found that inferred segments of IBD contain information about effective population size from around 4 generations to around 50 generations ago for SNP array data and to over 200 generations ago for sequence data. In human populations that we examined, the estimates of effective size were approximately one-third of the census size. We estimate the effective population size of European-ancestry individuals in the UK four generations ago to be eight million and the effective population size of Finland four generations ago to be 0.7 million. Our method is implemented in the open-source IBDNe software package.


Assuntos
Cromossomos/genética , Genética Populacional/métodos , Modelos Genéticos , Densidade Demográfica , Software , Simulação por Computador , Finlândia , Humanos , Desequilíbrio de Ligação , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
20.
Sci Rep ; 5: 8484, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25719731

RESUMO

Selective breeding has strongly reduced the genetic diversity in livestock species, and contemporary breeding practices exclude potentially beneficial rare genetic variation from the future gene pool. Here we test whether important traits arising by new mutations can be identified and rescued in highly selected populations. We screened milks from 2.5 million cows to identify an exceptional individual which produced milk with reduced saturated fat content, and improved unsaturated and omega-3 fatty acid concentrations. The milk traits were transmitted dominantly to her offspring, and genetic mapping and genome sequencing revealed a new mutation in a previously unknown splice enhancer of the DGAT1 gene. Homozygous carriers show features of human diarrheal disorders, and may be useful for the development of therapeutic strategies. Our study demonstrates that high-throughput phenotypic screening can uncover rich genetic diversity even in inbred populations, and introduces a novel strategy to develop novel milks with improved nutritional properties.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Leite/metabolismo , Mutação de Sentido Incorreto , Animais , Sequência de Bases , Bovinos/genética , Ácidos Graxos/biossíntese , Feminino , Estudos de Associação Genética , Metabolismo dos Lipídeos/genética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único
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