Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P <5 x 10(-8), false discovery rate <0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.Peer reviewe

Increased Risk of Herpes Zoster in Diabetic Patients Comorbid with Coronary Artery Disease and Microvascular Disorders: A Population-Based Study in Taiwan.

We investigated the association between the risk of herpes zoster (HZ) and diabetes-related macrovascular comorbidities and microvascular disorders in diabetic patients. This retrospective study included 25,345 patients with newly identified HZ and age- and gender-matched controls retrieved from the National Health Insurance Research Database in Taiwan during the period of 2005 to 2011. Multivariate logistic regression analyses were used to calculate the odds ratios (OR) and to assess the risk factors for HZ in diabetic patients with associated macrovascular or microvascular disorders. Risk factors for HZ were significantly increased in cases of diabetes mellitus (DM) compared with those in cases of non-DM controls (20.2% vs. 17.0%, OR = 1.24, p<0.001). Results of age- and gender-adjusted analyses demonstrated a significantly higher risk of HZ in DM patients with accompanying coronary artery disease (CAD) (adjusted OR = 1.21, p<0.001) and microvascular disorders (aOR = 1.32, p<0.001) than in DM patients with other comorbidities but no microvascular disorders. Patients who took thiazolidinedione, alpha-glucosidase inhibitors and insulin had a higher HZ risk than those taking metformin or sulphonylureas alone (aOR = 1.11, 1.14 and 1.18, p<0.001, respectively). Patients who took insulin alone or in combination with other antidiabetic agents had a significantly higher risk of HZ (aOR = 1.25, p<0.001) than those who received monotherapy. Diabetic patients comorbid with coronary artery disease and associated microvascular disorders had an increased risk of HZ occurrence

Flowchart for data retrieval of patients diagnosed with herpes zoster (HZ) and controls from the National Health Insurance Research Database in Taiwan from 2005 to 2011.

<p>LHID = Longitudinal Health Insurance Database.</p

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. Methods & findings Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, p = 3 × 10−29); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids

T2D prediction, glycemic genetic score.

<p>Forest plot of association between glycemic genetic score with incident T2D over a decade-long follow-up period, by ancestry. MESA (European and Asian ancestry) and the <i>G6PD</i> variant (rs1050828) in ARIC (European and African American) were not included in the discovery GWAS analysis. Effect estimates were combined in a fixed effects meta-analysis. Overall effect estimate: 1.05, 95% CI 1.04–1.06, <i>p</i> = 2.5 × 10⁻²⁹. ARIC, Atherosclerosis Risk in Communities Study; ES, Effect Size; FHS, Framingham Heart Study; GWAS, genome-wide association study; G6PD, glucose-6-phosphate dehydrogenase; I-Squared, Higgin's I-squared statistic, a measure of heterogeneity; MESA, Multiethnic Study of Atherosclerosis; SCHS, Singapore Chinese Health Study; T2D, type 2 diabetes.</p

Reclassification of individuals with discordant T2D status based on prevailing diagnostic thresholds for FG and HbA1c before and after accounting for the effect of erythrocytic variants.

<p>Reclassification of individuals with discordant T2D status based on prevailing diagnostic thresholds for FG and HbA1c before and after accounting for the effect of erythrocytic variants.</p

Mean HbA1c of individuals at the bottom 5% and top 5% of the distribution of ancestry-specific genetic scores and rs1050828 by genotype.

<p>The difference in measured HbA1c of individuals at the bottom 5% and top 5% of the distribution of an ancestry-specific additive GS composed of all 60 variants (GS-Total), and the equivalent calculation for an ancestry-specific GS composed of up to 20 erythrocytic variants (GS-E). Far right of the figure shows the mean HbA1c by genotype for chromosome X rs1050828. AA men, African American men; AA women, African American women; HbA1c, glycated hemoglobin; GS, genetic scores.</p