👤 F Schick

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. Show less

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis. Show less

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases. Show less

Genetic variants in genes encoding components of lipid metabolism have been associated with AMD. The aims of this study were to evaluate the relation of these genetic variants with serum lipid levels in AMD in a large case-control cohort (n = 3070) and to test for correlations between lipids and complement activation. Single nucleotide polymorphisms (SNPs) in eight lipid metabolism genes, previously described to be associated with AMD, were genotyped and tested for their association in our case-control cohort. Serum apolipoprotein B (ApoB), apolipoprotein AI (Apo-AI), cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDLC), and complement activation levels (C3d/C3) were measured and tested for association with AMD. Non-HDL cholesterol and LDL were inferred based on the measurements of the other lipids and lipoproteins. General linear models and χ2 tests were used to evaluate the relation of SNPs and lipids/lipoproteins to the disease as well as their interrelations. Significant genotypic associations with AMD were observed for SNPs in CETP, APOE, and FADS1. The serum levels of Apo-AI and HDLC were significantly higher in patients compared with controls. Triglycerides (TG) levels were lower in AMD compared with controls. A cumulative effect was observed for APOE and CETP genotypes on HDLC and Apo-AI levels. Complement activation levels correlated positively with HDLC and Apo-AI, and negatively with TG. Both the lipids/lipoproteins and the complement activation levels associate independently to AMD. This study bridges the gap between genetic associations and physiological lipid levels in AMD. Additionally, the observed correlations between complement activation and lipid levels link two major systems that previously were always assessed independently. Show less

It has not been solved whether subjects carrying the minor alleles of the -455T>C or -482C>T single nucleotide polymorphisms (SNPs) in the apolipoprotein-C3-gene (APOC3) have an increased risk for developing fatty liver and insulin resistance. We investigated the relationships of the SNPs with hepatic APOC3 expression and hypothesized that visceral obesity may modulate the effects of these SNPs on liver fat and insulin sensitivity (IS). APOC3 mRNA expression and triglyceride content were determined in liver biopsies from 50 subjects. In a separate group (N=330) liver fat was measured by (1)H-magnetic resonance spectroscopy. IS was estimated during an oral glucose tolerance test (OGTT) and the euglycemic, hyperinsulinemic clamp (N=222). APOC3 mRNA correlated positively with triglyceride content in liver biopsies (r=0.29, P=0.036). Carriers of the minor alleles (-455C and -482T) tended to have higher hepatic APOC3 mRNA expression (1.80 (0.45-3.56) vs 0.77 (0.40-1.64), P=0.09), but not higher triglyceride content (P=0.76). In 330 subjects the genotype did not correlate with liver fat (P=0.97) or IS (OGTT: P=0.41; clamp: P=0.99). However, a significant interaction of the genotype with waist circumference in determining liver fat was detected (P=0.02) in which minor allele carriers had higher liver fat only in the lowest tertile of waist circumference (P=0.01). In agreement, during a 9-month lifestyle intervention the minor allele carriers of the SNP -482C>T in the lowest tertile also had less decrease in liver fat (P=0.04). APOC3 mRNA expression is increased in fatty liver and is regulated by SNPs in APOC3. The impact of the APOC3 SNPs on fatty liver is small and depends on visceral obesity. Show less