Unique genetic architecture of CSF and brain metabolites pinpoints the novel targets for the traits of human wellness

Abstract

Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson's Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.

Figure 1. Mapping genetic regulators for metabolite level in CSF and brain identifies reported and novel association relationships and genetic loci.

a, Schematic overview for MGWAS identification and replication. b, CSF combined Manhattan plot. The x axis denotes the chromosome and positions. The red line represents multiple test corrected significance threshold P = 2.79 × 10⁻¹⁰. c, Brain combined Manhattan plot. The x axis denotes the chromosome and positions. The red line represents multiple test corrected significance threshold P = 1.74 × 10⁻¹⁰. d, Replication using multiple tissues we identified the number of reported and novel associations and loci for both CSF and brain. Novel signal in replicated association region was identified if non-colocalized (PP.H4 <= 0.6). The association A/B indicates: A: association region B: independent association signal.

Figure 2. The characteristics of metabolite quantitative trait loci.

a(d), Visualization of metabolites to loci associations in CSF and brain. The metabolites are ranked in y-axis based on their super pathways. Dots indicate the 192 association regions using their index variants. The pleiotropic regions were highlighted in orange. Pleiotropic regions were indicated by black vertical lines. b(e), Pleiotropy effect of CSF and brain metabolites quantitative trait loci. Each pleiotropic region (associated with more than one metabolite) was listed in the x axis. c(f), Metabolite polygenicity characterization in CSF and brain. Each metabolite was listed in the x axis.

Figure 3. Functional characterization of genetic regions associated with CSF and brain metabolite levels.

a, Identification of effector genes for the CSF MGWAS. b, Identification of effector genes of brain MGWAS. c, Distribution of functional annotations of CSF metabolite association signals. d, Distribution of functional annotations of brain metabolite association signals. e, Comparison of absolute effect size amongst impact level of the CSF association signals. f, Comparison of absolute effect size across impact levels of the brain association signals. g, Comparison of CSF signals’ effect size with minor allele frequency (MAF). h, Comparison of brain signals’ effect size with minor allele frequency (MAF).

Figure 4. Associated or causal relationships between metabolites and complex traits/disease uncover insights into etiology.

The plot showed associations between metabolite levels and traits identified from Metabolome-wide association study (MWAS) using CSF (top) and brain (bottom). Direction of effect and the strength of associations by P-value were represented by a range of colors. Colocalization were performed on each genetic locus through which the MWAS association were identified. Mendelian randomization (MR) tested all CSF metabolites with at least one association signal for all selected traits. The black bordered blocks illustrate significant findings from MR that passed FDR-correction. Metabolites, either monogenic (shown by metabolite name) or polygenic (shown by ‘metabolite_chromosome’ to specify the genetic region) were annotated by drug interests and effector gene categories.