X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1.

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits.

The genetic background shapes the susceptibility to mitochondrial dysfunction and NASH progression.

Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene-environment interactions. We tested the susceptibility of seven mouse strains to develop NASH.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

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 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.

The power of genetic diversity in genome-wide association studies of lipids.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels, heart disease remains the leading cause of death worldwide. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease.

Using off-target data from whole-exome sequencing to improve genotyping accuracy, association analysis and polygenic risk prediction.

Whole-exome sequencing (WES) has been widely used to study the role of protein-coding variants in genetic diseases. Non-coding regions, typically covered by sparse off-target data, are often discarded by conventional WES analyses. Here, we develop a genotype calling pipeline named WEScall to analyse both target and off-target data.

Association of variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

Objective: Hemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The Asahi variant which causes glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to lower HbA1c independently of glycemia in African ancestry populations. As different variants occur in Asian ancestry, we sought to identify Asian-specific variants associated with HbA1c.

The Use of Genomics to Drive Kidney Disease Drug Discovery and Development.

As opposed to diseases such as cancer, autoimmune disease, and diabetes, identifying drugs to treat CKD has proven significantly more challenging. Over the past 2 decades, new potential therapeutic targets have been identified as genetically altered proteins involved in rare monogenetic kidney diseases. Other possible target genes have been implicated through common genetic polymorphisms associated with CKD in the general population.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178).

Discovering metabolic disease gene interactions by correlated effects on cellular morphology.

Objective: Impaired expansion of peripheral fat contributes to the pathogenesis of insulin resistance and Type 2 Diabetes (T2D). We aimed to identify novel disease-gene interactions during adipocyte differentiation.

Methods: Genes in disease-associated loci for T2D, adiposity and insulin resistance were ranked according to expression in human adipocytes.

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants.

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model.

Phenome-wide association studies across large population cohorts support drug target validation.

Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints.

Relation of plasma ceramides to visceral adiposity, insulin resistance and the development of type 2 diabetes mellitus: the Dallas Heart Study.

Aims/hypothesis: Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort.

Methods: A total of 1557 participants in the Dallas Heart Study without type 2 diabetes underwent measurements of metabolic biomarkers, fat depots by MRI and plasma ceramides by liquid chromatography-mass spectrometry.

DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates.

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.