A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

BACKGROUND:Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.METHODS:In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency [greater than or equal to]10%, genotypic call rate [greater than or equal to]80%, and Hardy-Weinberg equilibrium p [greater than or equal to] 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).RESULTS:Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.CONCLUSION:Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., < 1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.

Christian Witness on the Plateau Vivarais-Lignon: Narrative, Nonviolence, and the Formation of Character

This dissertation analyzes the theological and ethical convictions that led the people of the Plateau Vivarais-Lignon to shelter thousands of refugees between 1939 and 1945. It does so by examining the themes of narrative identity, hospitality, character formation, nonviolence, and the contextual witness of church tradition. Though a number of studies have been published about the rescue activity in this region of France during World War II, none have thoroughly analyzed the theological nature of this activity. Using the Plateau Vivarais-Lignon as a case study in theological ethics, the dissertation draws on historical sources as well as the work of contemporary theologians and ethicists to understand, interpret, and analyze the witness of this community. After situating its rescue and resistance work within the Huguenot narrative of persecution and exile, I examine the theological convictions of the Reformed pastor of Le Chambon-sur-Lignon, André Trocmé, who played a key role in making the Plateau a place of refuge during the Holocaust. The study highlights the importance of narrative in the actions of this community and discusses the relationship between narrative, character, and ethics. It then examines the nonviolent commitments of key leaders of the rescue effort, using this analysis as a springboard to engage in broader theological reflection about the ethics of nonviolence. After examining the radical hospitality practiced on the Plateau in light of biblical narratives and Reformed history, I investigate the counter-cultural nature of Christian hospitality. The study concludes by analyzing the nature and witness of the church in light of the legacy of the Plateau Vivarais-Lignon. The dissertation suggests that increased academic and ecclesial attention be given to the relationship between narrative and character, the counter-cultural shape of Christian hospitality, and the active nature of nonviolence. It presents an in-depth analysis of the theological and ethical convictions of the people of the Plateau Vivarais-Lignon, arguing that their witness has ongoing significance for communities of faith as they grapple with how to form disciples, relate to the wider society, welcome strangers, and communicate God's shalom in a world of violence.