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Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
- Source :
- Nature communications, vol 12, iss 1
- Publication Year :
- 2021
- Publisher :
- eScholarship, University of California, 2021.
-
Abstract
- Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
- Subjects :
- Adult
Multifactorial Inheritance
Genotype
Prevention
Human Genome
Diabetes
Population
Biological Variation
Penetrance
Risk Assessment
Good Health and Well Being
Genetics
AMP-T2D-GENES Consortia
Diabetes Mellitus
2.1 Biological and endogenous factors
Humans
Genetic Predisposition to Disease
Exome
Genetic Testing
Aetiology
Metabolic and endocrine
Type 2
Biomarkers
Dyslipidemias
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature communications, vol 12, iss 1
- Accession number :
- edsair.dedup.wf.001..bf2cf6d0400cdcd8efed2796a0614c60