Variant level heritability estimates of type 2 diabetes in African Americans.

Type 2 diabetes (T2D) is caused by both genetic and environmental factors and is associated with an increased risk of cardiorenal complications and mortality. Though disproportionately affected by the condition, African Americans (AA) are largely underrepresented in genetic studies of T2D, and few estimates of heritability have been calculated in this race group. Using genome-wide association study (GWAS) data paired with phenotypic data from ~ 19,300 AA participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, Genetics of Hypertension Associated Treatments (GenHAT) study, and the Electronic Medical Records and Genomics (eMERGE) network, we estimated narrow-sense heritability using two methods: Linkage-Disequilibrium Adjusted Kinships (LDAK) and Genome-Wide Complex Trait Analysis (GCTA).

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer.

Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms.

Genes act in concert with each other in specific contexts to perform their functions. Determining how these genes influence complex traits requires a mechanistic understanding of expression regulation across different conditions. It has been shown that this insight is critical for developing new therapies.

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.

Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1.

A major goal of genetics research is to elucidate mechanisms explaining how genetic variation contributes to phenotypic variation. The genetic variants identified in genome-wide association studies (GWASs) generally explain only a small proportion of heritability of phenotypic traits, the so-called missing heritability problem. Recent evidence suggests that additional common variants beyond lead GWAS variants contribute to phenotypic variation; however, their mechanistic underpinnings generally remain unexplored.

Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results.

Purpose: We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results.

Methods: Participants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits.

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD.

Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations.

Background: Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent.

Multiancestral polygenic risk score for pediatric asthma.

Background: Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.

Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities.

Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study.

Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery.

Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate IRF8 expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for IRF8 that spatially interacts with the IRF8 promoter.

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.

Validation of low-coverage whole-genome sequencing for mitochondrial DNA variants suggests mitochondrial DNA as a genetic cause of preterm birth.

Preterm birth (PTB), or birth that occurs earlier than 37 weeks of gestational age, is a major contributor to infant mortality and neonatal hospitalization. Mutations in the mitochondrial genome (mtDNA) have been linked to various rare mitochondrial disorders and may be a contributing factor in PTB given that maternal genetic factors have been strongly linked to PTB. However, to date, no study has found a conclusive connection between a particular mtDNA variant and PTB.

Genome-wide association studies of low back pain and lumbar spinal disorders using electronic health record data identify a locus associated with lumbar spinal stenosis.

Identifying genetic risk factors for lumbar spine disorders may lead to knowledge regarding underlying mechanisms and the development of new treatments. We conducted a genome-wide association study involving 100,811 participants with genotypes and longitudinal electronic health record data from the Electronic Medical Records and Genomics Network and Geisinger Health. Cases and controls were defined using validated algorithms and clinical diagnostic codes.

SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression.

Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter.