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1.
Nat Genet ; 51(11): 1652-1659, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31676866

RESUMEN

Short tandem repeats (STRs) have been implicated in a variety of complex traits in humans. However, genome-wide studies of the effects of STRs on gene expression thus far have had limited power to detect associations and provide insights into putative mechanisms. Here, we leverage whole-genome sequencing and expression data for 17 tissues from the Genotype-Tissue Expression Project to identify more than 28,000 STRs for which repeat number is associated with expression of nearby genes (eSTRs). We use fine-mapping to quantify the probability that each eSTR is causal and characterize the top 1,400 fine-mapped eSTRs. We identify hundreds of eSTRs linked with published genome-wide association study signals and implicate specific eSTRs in complex traits, including height, schizophrenia, inflammatory bowel disease and intelligence. Overall, our results support the hypothesis that eSTRs contribute to a range of human phenotypes, and our data should serve as a valuable resource for future studies of complex traits.


Asunto(s)
Regulación de la Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Repeticiones de Microsatélite/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Estatura/genética , Biología Computacional , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Enfermedades Inflamatorias del Intestino/genética , Inteligencia/genética , Esquizofrenia/genética
2.
Nat Commun ; 9(1): 4397, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30353011

RESUMEN

Short tandem repeats (STRs) are involved in dozens of Mendelian disorders and have been implicated in complex traits. However, genotyping arrays used in genome-wide association studies focus on single nucleotide polymorphisms (SNPs) and do not readily allow identification of STR associations. We leverage next-generation sequencing (NGS) from 479 families to create a SNP + STR reference haplotype panel. Our panel enables imputing STR genotypes into SNP array data when NGS is not available for directly genotyping STRs. Imputed genotypes achieve mean concordance of 97% with observed genotypes in an external dataset compared to 71% expected under a naive model. Performance varies widely across STRs, with near perfect concordance at bi-allelic STRs vs. 70% at highly polymorphic repeats. Imputation increases power over individual SNPs to detect STR associations with gene expression. Imputing STRs into existing SNP datasets will enable the first large-scale STR association studies across a range of complex traits.


Asunto(s)
Genoma Humano , Haplotipos/genética , Repeticiones de Microsatélite/genética , Alelos , Variación Genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Estándares de Referencia
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