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Distinguishing genetic correlation from causation across 52 diseases and complex traits
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Journal Article
Distinguishing genetic correlation from causation across 52 diseases and complex traits
2018
Overview
Mendelian randomization, a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable mediates the genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the latent causal variable, quantified using the genetic causality proportion. We fit this model using mixed fourth moments
E
(
α
1
2
α
1
α
2
)
and
E
α
2
2
α
1
α
2
of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large
α
1
2
) will have correlated effects on trait 2 (large
α
1
α
2
), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike Mendelian randomization. Across 52 traits (average
n
= 331,000), we identified 30 causal relationships with high genetic causality proportion estimates. Novel findings included a causal effect of low-density lipoprotein on bone mineral density, consistent with clinical trials of statins in osteoporosis.
This study presents a new latent causal variable (LCV) model that distinguishes between genetic correlation and causation. Applying LCV to genome-wide association summary statistics for 52 traits identified genetically causal effects for 59 pairs of traits.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 45/43
/ 631/208
/ Animal Genetics and Genomics
/ Autistic Disorder - epidemiology
/ Autistic Disorder - genetics
/ Biomedical and Life Sciences
/ Etiology
/ Genetic Predisposition to Disease
/ Genomes
/ Genomics
/ Genotype
/ Humans
/ Hypothyroidism - epidemiology
/ Methods
/ Multifactorial Inheritance - genetics
/ Myocardial Infarction - epidemiology
/ Myocardial Infarction - genetics
/ Polymorphism, Single Nucleotide
/ Single-nucleotide polymorphism
/ Statins
