Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide... Show moreIntroduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 x 10(-8)) and suggestive (p < 1 x 10(-6)) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects. Show less
Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently... Show moreBackground: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk. Show less
Background: Precise preoperative planning improves postoperative outcomes in total hip arthroplasty (THA), especially in developmental dysplasia of the hip (DDH) cases. Previous studies used the T... Show moreBackground: Precise preoperative planning improves postoperative outcomes in total hip arthroplasty (THA), especially in developmental dysplasia of the hip (DDH) cases. Previous studies used the T-line and midcortical-line as preoperative landmarks to predict postoperative stem anteversion (PSA). However, the most reliable landmark in predicting PSA in DDH patients remains unclear. To find the most reliable measurement to predict the PSA in DDH patients, this study compared the midcortical-line and T-line at different femoral neck levels. Methods: Pre-and postoperative Computed Tomography (CT) scans of 28 hips in 21 DDH patients who received THA were obtained for three-dimensional femoral models. The preoperative CT scan was used to measure the anteversion of the midcortical-line on the axial cross-sectional plane images (AM-CT), the anteversion of the midcortical-line from 3D models (AM-3D), and the T-line from 3D models (AT-3D) at simulated osteotomy planes at 5 and 10 mm heights proximal to the base of the lesser trochanter. The correlation between the preoperative femoral anteversion (AM-CT, AM-3D, AT-3D) and the PSA was assessed to evaluate the prediction accuracy. Results: The correlations between the AM-CT and the PSA were 0.86 (mean difference (MD) = 1.9 degrees) and 0.92 (MD = -3.0 degrees) at 5 and 10 mm heights, respectively. The correlation between the AM-3D and the PSA were 0.71 (MD = -11.6 degrees) and 0.61 (MD = -12.9 degrees) at 5 and 10 mm heights. The AT-3D was significantly greater (MD = 15.4 degrees) than the PSA (p-value < 0.01) at 5 mm cutting height, and the correlation between the AT-3D and the PSA was 0.57 (MD = 7.8 degrees) at 10 mm cutting height. Conclusions: The AM-CT at the 10 mm height had the strongest correlation with the PSA and was more reliable in predicting the PSA when compared with the AM-3D and the AT-3D in DDH patients. Show less
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions... Show moreCommon single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries. Show less
Park, J.; Desjardins, B.; Liang, J.J.; Zghaib, T.; Xie, S.L.; Lucena-Padros, I.; ... ; Nazarian, S. 2020
Introduction The association of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) with epicardial and surface ventricular tachycardia (VT) electrogram features, in nonischemic... Show moreIntroduction The association of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) with epicardial and surface ventricular tachycardia (VT) electrogram features, in nonischemic cardiomyopathy (NICM), is unknown. We sought to define the association of LGE and viable wall thickness with epicardial electrogram features and exit site paced QRS duration in patients with NICM. Methods A total of 19 patients (age 53.5 +/- 11.5 years) with NICM (ejection fraction 40.2 +/- 13.2%) underwent CMR before VT ablation. LGE transmurality was quantified on CMR and coregistered with 2294 endocardial and 2724 epicardial map points. Results Both bipolar and unipolar voltage were associated with transmural signal intensity on CMR. Longer electrogram duration and fractionated potentials were associated with increased LGE transmurality, but late potentials or local abnormal ventricular activity were more prevalent in nontransmural versus transmural LGE regions (p < .05). Of all critical VT sites, 19% were located adjacent to regions with LGE but normal bipolar and unipolar voltage. Exit site QRS duration was affected by LGE transmurality and intramural scar location, but not by wall thickness, at the impulse origin. Conclusions In patients with NICM and VT, LGE is associated with epicardial electrogram features and may predict critical VT sites. Additionally, exit site QRS duration is affected by LGE transmurality and intramural location at the impulse origin or exit. Show less
Fuentes, L. de las; Sung, Y.J.; Noordam, R.; Winkler, T.; Feitosa, M.F.; Schwander, K.; ... ; Lifelines Cohort Study 2020
Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed... Show moreEducational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 x 10(-8)). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP. Show less
A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene... Show moreA person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. Show less
