Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits

Figures

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  Fig 1. The projected number of replicated loci and proportion of shared causative variants among the replicated loci. A total of 2,500 association peaks from well-powered GWAS studies (n = 150,000) were tested for the shared effect in simulated discovery cohorts (n = 10,000), and then select loci were tested for replication in simulated validation cohorts of the same genetic ancestry (n = 10,000–35,000). The candidate loci were identified by conditional false discovery rate (cFDR), colocalization tests (JLIM and eCAVIAR), or the intersection of cFDR and colocalization test. The p-value cutoff was set to 0.01 for cFDR and JLIM, and for eCAVIAR, the equivalent posterior threshold was calibrated using H0 simulation data. The 2,500 GWAS peaks consist of the loci simulating no causal effect for underpowered traits (H0) and those simulating the same causal effect between two traits (H1) or distinct causal effects (H2). The H1:H2 ratio was set to 1:19 (A and C) or 1:4 (B and D). The effect sizes of causative variants are correlated (ρ = 0.7) under H1 but uncorrelated under H2. Bonferroni correction was applied on replication tests. In Panel E, we contrast the number of replicated loci expected…

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  Fig 2. Pleiotropy at HK1 locus. A) Putatively pleiotropic locus linking a clinical trait (hematocrit) with an OSA trait (average SpO2). The evidence of shared effect between the clinical and OSA traits is significant (JLIM p = 4.2 x 10−4, FDR = 0.017). This SpO2 association replicates in validation cohorts after Bonferroni correction of 61 tests (p = 8.5 x 10−5). B) Pairwise comparison of–log10(p-values) between two traits confirms that the association signals are driven by the shared underlying effect. Each dot represents a SNP in the tested locus.

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  Fig 3. Candidate causal chains linking a clinical trait, OSA trait and gene expression. A) A candidate association in chromosome 12 with putative pleiotropic associations between the plateletcrit (clinical trait; red), AHI (OSA trait; blue) and expression of PRIM1 (DNA primase subunit 1) in monocytes (yellow). B) A candidate association in chromosome 16 with putative pleiotropic associations between the clinical trait FEV1/FVC (red), minimum O2 saturation (blue) and expression of MMP15 (matrix metallopeptidase 15) in lung (yellow).

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  Fig 4. Pleiotropic locus linking gene expression and an OSA related trait. A locus in chromosome 17 has associations between minimum oxygen saturation (blue) and expression of CHRNE (cholinergic receptor nicotinic epsilon subunit) in muscle tissues (yellow). Gene expression trait p-values and the appropriate gene in the locus are shown in yellow. Pairwise comparisons of–log10(p-values) between associated traits are shown in Panel B with matching colors in axis labels.