Large Bi-Ethnic Study of Plasma Proteome Leads to Comprehensive Mapping of cis-pQTL and Models for Proteome-wide Association Studies

Improved understanding of the genetic architecture of the proteome through studies of larger sample size, ethnic diversity, and advanced methods can facilitate the identification of causal mechanisms for complex traits. We conducted a comprehensive analysis of the common variant cis-regulatory genetic architecture of 4,665 plasma proteins or protein complexes ascertained using an aptamer-based technology from 7,213 European Americans (EA) and 1,871 African Americans (AA) from the Atherosclerosis Risk in Communities (ARIC) cohort study. We identified and fine-mapped 1,992 plasma proteins or protein complexes in EA and 1,605 in AA, with majority overlapping in EA, which had at least one significant single-nucleotide polymorphism (SNP) in cis region. Estimates of cis-heritability (cis-h2) for plasma proteins were similar across the two ethnic groups (median cis-h2 = 0.09 for EA and 0.10 for AA). Elastic-net based models for cis-SNP-based protein prediction produced high accuracy for the EA population (median R2/cis-h2=0.79), and notably for the AA (median R2/cis-h2 = 0.69), despite the much smaller sample size in the latter population. We illustrate the application of these models to conduct proteome-wide association studies (PWAS) for two related complex traits, serum urate and gout, and further conduct conditional analyses to interpret findings in the context of those from transcriptome-wide association studies (TWAS).

Evidence for specificity of polygenic contributions to attainment in English, maths and science during adolescence

How well one does at school is predictive of a wide range of important cognitive, socioeconomic, and health outcomes. The last few years have shown marked advancement in our understanding of the genetic contributions to, and correlations with, academic attainment. However, there exists a gap in our understanding of the specificity of genetic associations with performance in academic subjects during adolescence, a critical developmental period. To address this, the Avon Longitudinal Study of Parents and Children was used to conduct genome-wide association studies of standardised national English (N = 5983), maths (N = 6017) and science (N = 6089) tests. High SNP-based heritabilities (h2SNP) for all subjects were found (41–53%). Further, h2SNP for maths and science remained after removing shared variance between subjects or IQ (N = 3197–5895). One genome-wide significant single nucleotide polymorphism (rs952964, p = 4.86 × 10–8) and four gene-level associations with science attainment (MEF2C, BRINP1, S100A1 and S100A13) were identified. Rs952964 remained significant after removing the variance shared between academic subjects. The findings highlight the benefits of using environmentally homogeneous samples for genetic analyses and indicate that finer-grained phenotyping will help build more specific biological models of variance in learning processes and abilities.

Expression regulation of myo-inositol 3-phosphate synthase 1 (INO1) in determination of phytic acid accumulation in rice grain

Phytic acid (PA) is the primary phosphorus (P) storage compound in the seeds of cereals and legumes. Low PA crops, which are considered an effective way to improve grain nutrient availability and combat environmental issues relating to seed P have been developed using mutational and reverse genetics approaches. Here, we identify molecular mechanism regulating PA content among natural rice variants. First, we performed genome-wide association (GWA) mapping of world rice core collection (WRC) accessions to understand the genetic determinants underlying PA trait in rice. Further, a comparative study was undertaken to identify the differences in PA accumulation, protein profiles, and gene expression in low (WRC 5) and high PA (WRC 6) accessions. GWA results identified myo-inositol 3-phosphate synthase 1 (INO1) as being closely localized to a significant single nucleotide polymorphism. We found high rates of PA accumulation 10 days after flowering, and our results indicate that INO1 expression was significantly higher in WRC 6 than in WRC 5. Seed proteome assays found that the expression of INO1 was significantly higher in WRC 6. These results suggest that not only the gene itself but regulation of INO1 gene expression at early developmental stages is important in determining PA content in rice.

Abstract 90: The Atheroprotective Effects of Id3 Are Linked to B-1a Cell Proliferation and Plasma Levels of E06

Background: The HLH transcription factor, Id3, is essential for B cell-mediated atheroprotection in mice and a functionally significant single nucleotide polymorphism in the human ID3 gene at rs11574 is associated with carotid intimal medial thickness in humans. Yet, the mechanisms mediating Id3 atheroprotection are poorly understood. Recent studies provide clear evidence that B cell effects on atherosclerosis are subset dependent; with B2 cells promoting and B-1a cells attenuating atherosclerosis in a sIgM-dependent manner. Innate, natural IgM antibodies, such as E06, recognize oxidized phospholipids, are produced by B-1a cells, and inhibit atherogenesis. Therefore, we hypothesized that Id3 would regulate plasma levels of E06 IgM and atheroprotective B-1a cells. Methods & Results: Id3 -/- ApoE -/- mice (n = 9) at 8 weeks old had lower plasma levels of E06 compared to control Id3 +/+ ApoE -/- mice (n = 9) (1500 vs. 2750 RLU, p < 0.05) as measured by ELISA. This was not due to lower total IgM (270 vs. 100 ug/mL respectively, p < 0.05). ApoB-100 levels were not different (1500 vs 1600 RLU, n.s.). Consistent with plasma data, the number of B-1a cells, assessed by flow cytometry, was lower in Id3 -/- ApoE -/- (n = 5) compared to Id3 +/+ ApoE -/- mice (n = 4) (0.8 x10 5 vs 3.0 x10 5 , p < 0.05). There was no difference in transcript levels, as measured by real-time PCR, of E06 or sIgM in fluorescence-activated cell sorted B-1a cells. Furthermore, we found decreased homeostatic proliferation, measured by in situ CFSE dilution, of B-1a cells in Id3 -/- ApoE -/- mice (n = 5) compared to control mice (n = 5) (30.1% vs. 50.0%, p = 0.001). Additionally, humans with the functionally significant polymorphism in ID3 had lower plasma levels of IgM to MDA-LDL (n = 97, trend with p = 0.08) and no difference in IgG as measured by ELISA. Conclusion: Taken together, these data suggest a novel role for Id3 in regulating B-1a cell proliferation, resulting in reduced plasma levels of the atheroprotective natural antibody, E06. Moreover, the data suggest that the ID3 polymorphism in humans at rs11574 may link protective IgM to modified lipids with vascular disease.