Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

STRUCTURED ABSTRACT Objectives We evaluated whether carotid intima-media thickness (C-IMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF). Background Traditional CHD risk prediction schemes need further improvement as the majority of the CHD events occur in the “low” and “intermediate” risk groups. C-IMT and presence of plaque on an ultrasound are associated with CHD and therefore could potentially help improve CHD risk prediction. Methods Risk prediction models (overall, in men and women) considered included TRF-only, TRF+C-IMT, TRF+plaque, and TRF+C-IMT+ plaque. Model predictivity was determined by calculating the area under the receiver operating characteristic curve (AUC) adjusted for optimism. Cox-proportional hazards models were used to estimate 10-year CHD risk for each model, and the number of individuals reclassified determined. Observed events were compared with expected events; and, the net reclassification index (NRI) was calculated. Results Of 13,145 eligible individuals (5,682 men; 7,463 women), ~23% were reclassified by adding C-IMT+plaque information. Overall, the addition of C-IMT and plaque separately or together to the TRF model improved the AUC which increased from 0.742 to 0.750, 0.751 and 0.755 for the TRF-only, TRF+C-IMT, TRF+plaque and TRF+C-IMT+plaque model respectively. The C-IMT+TRF+plaque model had a NRI of 9.9% when compared to TRF-only in the overall population. However, comparison of TRF+C-IMT+plaque with TRF+C-IMT or TRF+plaque only resulted in non-significant or modestly significant changes of the various statistical tests. Sex-specific analyses are presented in the manuscript. Conclusion Adding plaque and C-IMT to TRF improves CHD risk prediction in the ARIC study.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

BRCA1 and BRCA2 are the two major identified causes of inherited breast cancer, with mutations in either gene conferring up to 80-90% lifetime risk of breast cancer in carrier females. Mutations in BRCA1 account for approximately 45% of familial breast cancer and 90% of inherited breast/ovarian cancer, whereas mutations in BRCA2 account for a comparable percentage of inherited breast cancer cases. Over 85 distinct BRCA1 mutations and a growing list of BRCA2 mutations have been identified, with the majority resulting in protein truncation. A specific BRCA1 mutation, 185delAG, has a reported increased carrier frequency of approximately 0.9% in the Ashkenazi Jewish population, but is also found in rare non-Jewish patients with a different haplotype. The 6174delT mutation in BRCA2 was recently identified as a frequent mutation in 8 out of 107 Ashkenazi Jewish women diagnosed with breast cancer by age 50 (ref. 8), as well as in three Ashkenazi male breast cancer patients. We have conducted a large-scale population study to investigate the prevalence of specific BRCA1 and BRCA2 mutations in Ashkenazi Jewish individuals who were unselected for breast cancer. BRCA1 mutation screening on approximately 3,000 Ashkenazi Jewish samples determined a carrier frequency of 1.09% for the 185delAG mutation and 0.13% for the 5382insC mutation. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation. This expanded population-based study confirms that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constitute the two most frequent mutation alleles predisposing to hereditary breast cancer among the Ashkenazim, and suggests a relatively lower penetrance for the 6174delT mutation in BRCA2.