RESUMEN
The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
Asunto(s)
Variación Genética/genética , Genética de Población/normas , Genoma Humano/genética , Genómica/normas , Internacionalidad , Conjuntos de Datos como Asunto , Demografía , Susceptibilidad a Enfermedades , Exoma/genética , Genética Médica , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación INDEL/genética , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Enfermedades Raras/genética , Estándares de Referencia , Análisis de Secuencia de ADNRESUMEN
We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factores de Transcripción de Tipo Kruppel/genética , Esquizofrenia/genética , Trastorno Bipolar/genética , Estudios de Casos y Controles , Mapeo Cromosómico , Estudios de Seguimiento , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Enfermedad , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Artritis Reumatoide/genética , Estudios de Casos y Controles , Enfermedad de Crohn/genética , Diabetes Mellitus/genética , Frecuencia de los Genes/genética , Humanos , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Proyectos Piloto , Polimorfismo de Nucleótido Simple/genética , Control de CalidadRESUMEN
The number of human genomes being genotyped or sequenced increases exponentially and efficient haplotype estimation methods able to handle this amount of data are now required. Here we present a method, SHAPEIT4, which substantially improves upon other methods to process large genotype and high coverage sequencing datasets. It notably exhibits sub-linear running times with sample size, provides highly accurate haplotypes and allows integrating external phasing information such as large reference panels of haplotypes, collections of pre-phased variants and long sequencing reads. We provide SHAPEIT4 in an open source format and demonstrate its performance in terms of accuracy and running times on two gold standard datasets: the UK Biobank data and the Genome In A Bottle.
Asunto(s)
Interpretación Estadística de Datos , Haplotipos , Programas Informáticos , Bancos de Muestras Biológicas , Conjuntos de Datos como Asunto , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Polimorfismo de Nucleótido Simple , Tamaño de la Muestra , Análisis de Secuencia de ADNRESUMEN
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Estudios de Casos y Controles , Mapeo Cromosómico , Femenino , Genes p16 , Proteínas de Homeodominio/genética , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Intrones , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores de Transcripción/genética , Reino UnidoRESUMEN
We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
Asunto(s)
Autoinmunidad/genética , Neoplasias de la Mama/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Espondilitis Anquilosante/genética , Tiroiditis Autoinmune/genética , Aminopeptidasas/genética , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Mapeo Cromosómico , Genética de Población , Genotipo , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento , Antígenos de Histocompatibilidad Menor , Esclerosis Múltiple/epidemiología , América del Norte/epidemiología , Reacción en Cadena de la Polimerasa , Receptores Inmunológicos/genética , Receptores de Interleucina/genética , Espondilitis Anquilosante/epidemiología , Tiroiditis Autoinmune/epidemiologíaRESUMEN
For fMRI time-series analysis to be statistically valid, it is important to deal correctly with temporal autocorrelation in the noise. Most of the approaches in the literature adopt a two-stage approach in which the autocorrelation structure is estimated using the residuals of an initial model fit. This estimate is then used to "prewhiten" the data and the model before the model is refit to obtain final activation parameter estimates. An assumption implicit in this scheme is that the residuals from the initial model fit represent a realization of the "true" noise process. In general this assumption will not be correct as certain components of the noise will be removed by the model fit. In this paper we examine (i) the form of the bias induced by the initial model fit, (ii) methods of correcting for the bias, and (iii) the impact of bias correction on the model parameter estimates. We find that while bias correction does result in more accurate estimates of the correlation structure, this does not translate into improved estimates of the model parameters. In fact estimates of the model parameters and their standard errors are seen to be so accurate that we conclude that bias correction is unnecessary.