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1.
PLoS Med ; 16(1): e1002724, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30605491

RESUMEN

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.


Asunto(s)
Carcinoma de Células Renales/etiología , Neoplasias Renales/etiología , Obesidad/complicaciones , Glucemia/análisis , Presión Sanguínea , Índice de Masa Corporal , Carcinoma de Células Renales/genética , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Insulina/sangre , Neoplasias Renales/genética , Lípidos/sangre , Masculino , Análisis de la Aleatorización Mendeliana , Obesidad/genética , Factores de Riesgo
2.
Nat Genet ; 51(3): 414-430, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30820047

RESUMEN

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aß processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Inmunidad/genética , Lípidos/genética , Proteínas tau/genética , Anciano , Estudios de Casos y Controles , Femenino , Pruebas Genéticas/métodos , Estudio de Asociación del Genoma Completo/métodos , Haplotipos/genética , Humanos , Metabolismo de los Lípidos/genética , Masculino
4.
Genetics ; 177(2): 1059-70, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17720924

RESUMEN

To evaluate and compare the extent of LD in cattle, 1536 SNPs, mostly localized on BTA03, were detected in silico from available sequence data using two different methods and genotyped on samples from 14 distinct breeds originating from Europe and Africa. Only 696 SNPs could be validated, confirming the importance of trace-quality information for the in silico detection. Most of the validated SNPs were informative in several breeds and were used for a detailed description of their genetic structure and relationships. Results obtained were in agreement with previous studies performed on microsatellite markers and using larger samples. In addition, the majority of the validated SNPs could be mapped precisely, reaching an average density of one marker every 311 kb. This allowed us to analyze the extent of LD in the different breeds. Decrease of LD with physical distance across breeds revealed footprints of ancestral LD at short distances (<10 kb). As suggested by the haplotype block structure, these ancestral blocks are organized, within a breed, into larger blocks of a few hundred kilobases. In practice, such a structure similar to that already reported in dogs makes it possible to develop a chip of <300,000 SNPs, which should be efficient for mapping purposes in most cattle breeds.


Asunto(s)
Bovinos/genética , Mapeo Cromosómico/métodos , Haplotipos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , África , Animales , Cruzamiento , Biología Computacional , Europa (Continente) , Genotipo , Repeticiones de Microsatélite
5.
Neurology ; 86(23): 2134-7, 2016 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-27037229

RESUMEN

OBJECTIVE: To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting. METHODS: We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls. RESULTS: After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)). CONCLUSIONS: These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Mutación , Anciano , Bélgica , Estudios de Casos y Controles , Exoma , Francia , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos
6.
Eur J Hum Genet ; 24(5): 710-6, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26242991

RESUMEN

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.


Asunto(s)
Enfermedad de Alzheimer/genética , Exoma , Pruebas Genéticas/métodos , Precursor de Proteína beta-Amiloide/genética , Estudios de Casos y Controles , Femenino , Pruebas Genéticas/normas , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Presenilina-1/genética , Presenilina-2/genética , Procesamiento Proteico-Postraduccional/genética
7.
Hum Mutat ; 24(6): 517-25, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15523649

RESUMEN

The region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathological diseases, including type 1 diabetes mellitus and rheumatoid arthritis. However, strong linkage disequilibrium across the MHC has hampered the identification of the precise genes involved. In addition, the observation of "blocks" of DNA in the MHC within which recombination is very rare, limits the resolution that may be obtained by genotyping individual SNPs. Hence a greater understanding of the haplotypes of the block spanning the TNF cluster is necessary. To this end, we genotyped 32 human leukocyte antigen (HLA)-homozygous workshop cell lines and 300 healthy control samples for 19 coding and promoter region SNPs spanning 45 kb in the central MHC near the TNF genes. The workshop cell lines defined 11 SNP haplotypes that account for approximately 80% of the haplotypes observed in the 300 control individuals. Using the control individuals, we defined a further six haplotypes that account for an additional 10% of donors. We show that the 17 haplotypes of the "TNF block" can be identified using 15 SNPs.


Asunto(s)
Complejo Mayor de Histocompatibilidad , Polimorfismo de Nucleótido Simple , Factores de Necrosis Tumoral/genética , Población Blanca/genética , Línea Celular Transformada , ARN Helicasas DEAD-box , Genotipo , Haplotipos , Humanos , Regiones Promotoras Genéticas , ARN Helicasas/genética
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