Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Quantitative single-cell proteomics as a tool to characterize cellular hierarchies

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. RANKL regulates male reproductive function

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Predictive Importance of Blood Pressure Characteristics With Increasing Age in Healthy Men and Women: The MORGAM Project

    Research output: Contribution to journalJournal articleResearchpeer-review

  • AMP-T2D-GENES Consortia
View graph of relations

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.

Original languageEnglish
Article number3505
JournalNature Communications
Volume12
Issue number1
Pages (from-to)3505
ISSN2041-1723
DOIs
Publication statusPublished - 9 Jun 2021

    Research areas

  • Adult, Biological Variation, Population, Biomarkers/metabolism, Diabetes Mellitus, Type 2/genetics, Dyslipidemias/genetics, Exome/genetics, Genetic Predisposition to Disease/genetics, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment

ID: 66479329