BACKGROUND: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.METHODS: We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants.RESULTS: As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P , .0001) more likely to carry one of these types of genetic susceptibility compared with controls.CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare

Climate dynamics are inextricably linked to processes in social systems that are highly unequal. This suggests a need for coupled social-climate models that capture pervasive real-world asymmetries in the population distribution of the consequences of anthropogenic climate change and climate (in)action. Here, we use evolutionary game theory to develop a social-climate model with group structure to investigate how anthropogenic climate change and population heterogeneity coevolve. We find that greater homophily and resource inequality cause an increase in the global peak temperature anomaly by as much as 0.7°C. Also, climate change can structure human populations by driving opinion polarization. Finally, climate mitigation achieved by reducing the cost of mitigation measures paid by individuals tends to be contingent upon socio-economic conditions, whereas policies that achieve communication between different strata of society show climate mitigation benefits across a broad socio-economic regime. We conclude that advancing climate change mitigation efforts can benefit from a social-climate systems perspective.

Climate dynamics are inextricably linked to processes in social systems that are highly unequal. This suggests a need for coupled social-climate models that capture pervasive real-world asymmetries in the population distribution of the consequences of anthropogenic climate change and climate (in)action. Here we develop a simple social-climate model with group structure to investigate how anthropogenic climate change and population heterogeneity co-evolve. We find that greater homophily and resource inequality cause an increase in the global peak temperature anomaly by as much as 0.7°C. Also, climate change can structure human populations by driving opinion polarization. Finally, climate mitigation achieved by reducing the cost of mitigation measures paid by individuals tends to be contingent upon socio-economic conditions, whereas policies that achieve communication between different strata of society show climate mitigation benefits across a broad socio-economic regime. We conclude that advancing climate change mitigation efforts can benefit from a social-climate systems perspective.

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