Estimating clinical risk in gene regions from population sequencing cohort data.
Am J Hum Genet
; 110(6): 940-949, 2023 06 01.
Article
en En
| MEDLINE
| ID: mdl-37236177
ABSTRACT
While pathogenic variants can significantly increase disease risk, it is still challenging to estimate the clinical impact of rare missense variants more generally. Even in genes such as BRCA2 or PALB2, large cohort studies find no significant association between breast cancer and rare missense variants collectively. Here, we introduce REGatta, a method to estimate clinical risk from variants in smaller segments of individual genes. We first define these regions by using the density of pathogenic diagnostic reports and then calculate the relative risk in each region by using over 200,000 exome sequences in the UK Biobank. We apply this method in 13 genes with established roles across several monogenic disorders. In genes with no significant difference at the gene level, this approach significantly separates disease risk for individuals with rare missense variants at higher or lower risk (BRCA2 regional model OR = 1.46 [1.12, 1.79], p = 0.0036 vs. BRCA2 gene model OR = 0.96 [0.85, 1.07] p = 0.4171). We find high concordance between these regional risk estimates and high-throughput functional assays of variant impact. We compare our method with existing methods and the use of protein domains (Pfam) as regions and find REGatta better identifies individuals at elevated or reduced risk. These regions provide useful priors and are potentially useful for improving risk assessment for genes associated with monogenic diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Predisposición Genética a la Enfermedad
Tipo de estudio:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Am J Hum Genet
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos