Genetic and modifiable risk factors combine multiplicatively in common disease.
Coronary artery disease
Genome-wide association studies
Liability threshold
Risk prediction
Risk score
Journal
Clinical research in cardiology : official journal of the German Cardiac Society
ISSN: 1861-0692
Titre abrégé: Clin Res Cardiol
Pays: Germany
ID NLM: 101264123
Informations de publication
Date de publication:
Feb 2023
Feb 2023
Historique:
received:
27
04
2022
accepted:
02
08
2022
pubmed:
21
8
2022
medline:
8
2
2023
entrez:
20
8
2022
Statut:
ppublish
Résumé
The joint contribution of genetic and environmental exposures to noncommunicable diseases is not well characterized. We modeled the cumulative effects of common risk alleles and their prevalence variations with classical risk factors. We analyzed mathematically and statistically numbers and effect sizes of established risk alleles for coronary artery disease (CAD) and other conditions. In UK Biobank, risk alleles counts in the lowest (175.4) and highest decile (205.7) of the distribution differed by only 16.9%, which nevertheless increased CAD prevalence 3.4-fold (p < 0.01). Irrespective of the affected gene, a single risk allele multiplied the effects of all others carried by a person, resulting in a 2.9-fold stronger effect size in the top versus the bottom decile (p < 0.01) and an exponential increase in risk (R > 0.94). Classical risk factors shifted effect sizes to the steep upslope of the logarithmic function linking risk allele numbers with CAD prevalence. Similar phenomena were observed in the Estonian Biobank and for risk alleles affecting diabetes mellitus, breast and prostate cancer. Alleles predisposing to common diseases can be carried safely in large numbers, but few additional ones lead to sharp risk increments. Here, we describe exponential functions by which risk alleles combine interchangeably but multiplicatively with each other and with modifiable risk factors to affect prevalence. Our data suggest that the biological systems underlying these diseases are modulated by hundreds of genes but become only fragile when a narrow window of total risk, irrespective of its genetic or environmental origins, has been passed.
Sections du résumé
BACKGROUND
BACKGROUND
The joint contribution of genetic and environmental exposures to noncommunicable diseases is not well characterized.
OBJECTIVES
OBJECTIVE
We modeled the cumulative effects of common risk alleles and their prevalence variations with classical risk factors.
METHODS
METHODS
We analyzed mathematically and statistically numbers and effect sizes of established risk alleles for coronary artery disease (CAD) and other conditions.
RESULTS
RESULTS
In UK Biobank, risk alleles counts in the lowest (175.4) and highest decile (205.7) of the distribution differed by only 16.9%, which nevertheless increased CAD prevalence 3.4-fold (p < 0.01). Irrespective of the affected gene, a single risk allele multiplied the effects of all others carried by a person, resulting in a 2.9-fold stronger effect size in the top versus the bottom decile (p < 0.01) and an exponential increase in risk (R > 0.94). Classical risk factors shifted effect sizes to the steep upslope of the logarithmic function linking risk allele numbers with CAD prevalence. Similar phenomena were observed in the Estonian Biobank and for risk alleles affecting diabetes mellitus, breast and prostate cancer.
CONCLUSIONS
CONCLUSIONS
Alleles predisposing to common diseases can be carried safely in large numbers, but few additional ones lead to sharp risk increments. Here, we describe exponential functions by which risk alleles combine interchangeably but multiplicatively with each other and with modifiable risk factors to affect prevalence. Our data suggest that the biological systems underlying these diseases are modulated by hundreds of genes but become only fragile when a narrow window of total risk, irrespective of its genetic or environmental origins, has been passed.
Identifiants
pubmed: 35987817
doi: 10.1007/s00392-022-02081-4
pii: 10.1007/s00392-022-02081-4
pmc: PMC9898372
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
247-257Subventions
Organisme : the Australian National Health
ID : 1113400
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : German Federal Ministry of Education and Research
ID : 01KL1802
Organisme : German Federal Ministry of Education and Research
ID : ZF4590201BA8
Organisme : German Federal Ministry of Education and Research
ID : 01ZX1706C
Organisme : the Australian National Health
ID : FL180100072
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : the Australian National Health
ID : DE200100425
Organisme : German Federal Ministry of Education and Research
ID : 16GW0198K
Informations de copyright
© 2022. The Author(s).
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