An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.
Nat Genet
; 50(5): 727-736, 2018 04 26.
Article
en En
| MEDLINE
| ID: mdl-29700473
ABSTRACT
Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Predisposición Genética a la Enfermedad
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Isoformas de Proteínas
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Polimorfismo de Nucleótido Simple
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Mutación INDEL
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Trastorno del Espectro Autista
Tipo de estudio:
Risk_factors_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos