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

• 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).

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)