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Leif Groop

Leif Groop

Principal investigator

Leif Groop

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


  • J.K. Goodrich
  • Leif Groop
  • Peter M Nilsson
  • Tiinamaija Tuomi
  • M.S. Udler

Summary, in English

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. © 2021, The Author(s).


  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Internal Medicine - Epidemiology
  • EpiHealth: Epidemiology for Health
  • Diabetic Complications

Publishing year





Nature Communications





Document type

Journal article


Nature Publishing Group


  • Endocrinology and Diabetes


  • database
  • detection method
  • disease severity
  • epidemiology
  • gene expression
  • genetic variation
  • genotype
  • adult
  • Article
  • case control study
  • cohort analysis
  • controlled study
  • dyslipidemia
  • effect size
  • exome
  • genetic risk score
  • genetic variability
  • heredity
  • human
  • major clinical study
  • monogenic disorder
  • non insulin dependent diabetes mellitus
  • penetrance
  • phenotype
  • whole exome sequencing
  • biological variation
  • genetic predisposition
  • genetics
  • metabolism
  • multifactorial inheritance
  • risk assessment
  • biological marker
  • Adult
  • Biological Variation, Population
  • Biomarkers
  • Diabetes Mellitus, Type 2
  • Dyslipidemias
  • Exome
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Multifactorial Inheritance
  • Penetrance
  • Risk Assessment



Research group

  • Genomics, Diabetes and Endocrinology
  • Internal Medicine - Epidemiology
  • Diabetic Complications


  • ISSN: 2041-1723