Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

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 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 &lt; 5 × 10−8) and suggestive (p &lt; 1 × 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.</p

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 1

Differentiation of Human Embryonic Stem Cells to Endothelial Progenitor Cells on Laminins in Defined and Xeno-free Systems

A major hurdle for in vitro culturing of primary endothelial cells (ECs) is that they readily dedifferentiate, hampering their use for therapeutic applications. Human embryonic stem cells (hESCs) may provide an unlimited cell source; however, most current protocols deriving endothelial progenitor cells (EPCs) from hESCs use direct differentiation approaches albeit on undefined matrices, yet final yields are insufficient. We developed a method to culture monolayer hESCs on stem cell niche laminin (LN) LN511 or LN521 matrix. Here, we report a chemically defined, xeno-free protocol for differentiation of hESCs to EPCs using LN521 as the main culture substrate. We were able to generate ∼95% functional EPCs defined as VEGFR2+CD34+CD31+VE-Cadherin+. RNA-sequencing analyses of hESCs, EPCs, and primary human umbilical vein endothelial cells showed differentiation-related EC expression signatures, regarding basement membrane composition, cell-matrix interactions, and changes in endothelial lineage markers. Our results may facilitate production of stable ECs for the treatment of vascular diseases and in vitro cell modeling

Regulation of the Boundaries of Accessible Chromatin

<div><p>Regulatory regions maintain nucleosome-depleted, open chromatin status but simultaneously require the presence of nucleosomes for specific histone modifications. It remains unclear how these can be achieved for proper regulatory function. Here we demonstrate that nucleosomes positioned within accessible chromatin regions near the boundaries provide platforms for histone modifications while preventing the occlusion of regulatory elements. These boundary nucleosomes were particularly enriched for active or poised regulatory marks in human, such as histone acetylations, H3K4 methylations, H3K9me3, H3K79me2, and H4K20me1. Additionally, we found that based on a genome-wide profiling of ∼100 recombinant yeast strains, the location of open chromatin borders tends to vary mostly within 150 bp upon genetic perturbation whereas this positional variation increases in proportion to the sequence preferences of the underlying DNA for nucleosome formation. More than 40% of the local boundary shifts were associated with genetic variation in <i>cis</i>- or <i>trans</i>-acting factors. A sizeable fraction of the identified genetic factors was also associated with nearby gene expression, which was correlated with the distance between the transcription start site (tss) and the boundary that faces the tss. Taken together, the variation in the width of accessible chromatin regions may arise in conjunction with the modulation of the boundary nucleosomes by post-translational modifications or by chromatin regulators and in association with the activity of nearby gene transcription.</p></div

Local changes of yeast open chromatin upon genetic perturbation.

<p>(A) We identified 4,897 open chromatin loci in BY4716 and aligned them by the 5′ end, center, and 3′ end, and then mapped the relative locations of nearby open chromatin loci in the other 95 strains. The center is defined as the middle point between the 5′ and 3′ boundaries. The number of strains (0∼95) that matches its boundary or center within a given distance from the homologous boundary or center in BY4716 was obtained and the frequency of the overlappings is represented as color gradient according to the distance shown at the bottom of each heat map. The rows of each heat map correspond to each of the 4,897 chromatin sites in BY4716. (B) The average frequency of mapped locations as a function of the distance to the center or to the end of the homologous site in BY4716. (C) The average frequency of mapped locations according to the <i>in vitro</i> nucleosome score as a function of the distance to the center or to the end of the homologous site in BY4716.</p

Histone modifications and H2A.Z occupancy across open chromatin in human.

<p>Shown is the body of open chromatin, which is divided into ten bins, along with 1(A) Pattern of H3K27ac, H3K4me2, H3K4me3, and H3K9ac. (B) Pattern of H3K4me1, H3K79me2, H3K9me3, and H4K20me1. (C) Pattern of H3K27me3 and H3K36me3.</p

Boundary nucleosome positioning within open chromatin.

<p>(A) Superposition of <i>in vivo</i> and <i>in vitro</i> nucleosomes surrounding the <i>in vivo</i> TFBSs (black curve) and sequence-predicted Transfac TFBSs (gray curve). (B) Number of DHS tags mapped to the region centered on the <i>in vivo</i> TFBSs (black curve) and sequence-predicted Transfac TFBSs (gray curve). (C) Chromatin structure in GM12878 at a genomic locus (chr2:232,378,500–232,379,800). Shown from top to bottom are tracks for open chromatin density (two replicates), chromatin states (red: active promoter, yellow: weak enhancer, and orange: strong enhancer), nucleosome density (blue box: boundary nucleosomes), histone modifications (density shown on the gray scale with dark indicating dense modifications), and TF binding locations (binding affinity shown on the same gray scale as above).</p

Positioning of boundary nucleosomes within open chromatin.

<p>(A) Superposition of <i>in vivo</i> and <i>in vitro</i> nucleosomes, and FAIRE read density across the boundaries of promoter-associated (left) or non-associated (right) open chromatin in yeast. (B) Superposition of <i>in vivo</i> and <i>in vitro</i> nucleosomes, and FAIRE read density across the boundaries of promoter-associated (left) or non-associated (right) open chromatin in human.</p