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Distinguishing genetic correlation from causation across 52 diseases and complex traits.

ABSTRACT: 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 [Formula: see text] and [Formula: see text] of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large [Formula: see text]) will have correlated effects on trait 2 (large ?1?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.

SUBMITTER: O'Connor LJ

PROVIDER: S-EPMC6684375 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Distinguishing genetic correlation from causation across 52 diseases and complex traits.

O'Connor Luke J LJ Price Alkes L AL

Nature genetics 20181029 12

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 [Formula: see text] and [Formula: see text] of marginal ef ...[more]

PMID: 30374074

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Project description:BackgroundAge-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits.MethodsFor each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression.ResultsOf the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values < 0.01, p values from < 1.0 × 10-16 to 1.9 × 10-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 × 10-7 to 3.0 × 10-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis.ConclusionsWe demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common.

Dataset Information

Distinguishing genetic correlation from causation across 52 diseases and complex traits.

Publications

Distinguishing genetic correlation from causation across 52 diseases and complex traits.

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