Suchergebnisse

Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P$_v$), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (P$_m$). Correlations between P$_v$ and P$_m$ were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When P$_v$ and P$_m$ were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P$_v$ distribution (P$_{binomial}$ <0.05). SNPs from the top 1% of the P$_m$ distribution for BMI had more significant Pv values (P$_{Mann-Whitney}$ = 1.46×10$^{-5}$), and the odds ratio of SNPs with nominally significant (<0.05) P$_m$ and P$_v$ was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (P$_{int}$<0.05) were enriched with nominally significant P$_v$ values (P$_{binomial}$ = 8.63×10$^{-9}$ and 8.52×10$^{-7}$ for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them. ; This research was undertaken as part of a research program supported by the European Commission (CoG-2015_681742_NASCENT), Swedish Research Council (Distinguished Young Researchers Award in Medicine), Swedish HeartLung Foundation, and the Novo Nordisk Foundation, all grants to PWF. DS is supported by the Swedish Research Council International Postdoc Fellowship (4.1-2016-00416). TVV is supported by the Novo Nordisk Foundation Postdoctoral Fellowship within Endocrinology/ Metabolism at International Elite Research Environments via NNF16OC0020698. TWW was supported by the grants "Bundesministerium fur Bildung und Forschung": BMBF-01ER1206, BMBF- 01ER1507. APM is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant WT098017). LAC acknowledges funding for the Framingham Heart Study: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 and Contract No. HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was partially supported by grant R01-DK089256 from the National Institute of Diabetes and Digestive and Kidney Diseases (MPIs: I.B. Borecki, LAC, K. North). TOK was supported by the Danish Council for Independent Research (DFF—1333-00124) and Sapere Aude program grant (DFF—1331-00730B). RM would like to acknowledge the High Performance Computing Center of University of Tartu. EGCUT was supported by EU H2020 grants 692145, 676550, 654248, 692065, Estonian Research Council Grant IUT20-60, and PerMed I NIASC, EIT—Health and European Union through the European Regional Development Fund (Project No, 2014-2020.4.01.15-0012 GENTRANSMED).