Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories.

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesize that rare variant burden over a large number of genes can be combined into a predictive rare variant genetic risk score (RVGRS). We propose a method (RV-EXCALIBER) that leverages summary-level data from a large public exome sequencing database (gnomAD) as controls and robustly calibrates rare variant burden to account for the aforementioned biases. A calibrated RVGRS strongly associates with coronary artery disease (CAD) in European and South Asian populations by capturing the aggregate effect of rare variants through a polygenic model of inheritance. The RVGRS identifies 1.5% of the population with substantial risk of early CAD and confers risk even when adjusting for known Mendelian CAD genes, clinical risk factors, and a common variant genetic risk score.

Marked Influence of Adiposity on Laboratory Biomarkers in a Healthy Cohort of Children and Adolescents.

BACKGROUND: The prevalence of pediatric obesity is increasing worldwide and strongly associates with metabolic abnormalities, including inflammation, insulin resistance, and dyslipidemia. This study assessed the influence of 3 measures of adiposity on levels of routinely assessed biochemical markers in apparently healthy children and adolescents. METHODS: The influence of adiposity on 35 biochemical markers was examined in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents by comparing serum biomarker levels between subjects with a normal weight, overweight, and obese body mass index (BMI). The cohort comprised 1332 subjects 5.1 to 19.0 years of age with a BMI ranging from 13.4 to 65.0 kg/m2. The association between each biochemical marker and BMI, waist circumference, and waist-to-height ratio z-scores was assessed, while adjusting for age and sex. Reference intervals were established for all biochemical markers before and after removing overweight/obese subjects. RESULTS: In children and adolescents, levels of 13 routinely assessed biochemical markers, including alanine aminotransferase, apolipoprotein B, complement components 3 and 4, cholinesterase, high sensitivity C-reactive protein, gamma-glutamyl transferase, haptoglobin, high-density lipoprotein cholesterol, iron, transferrin, triglycerides, and uric acid, were significantly different between BMI categories. BMI, waist circumference, and/or waist-to-height ratio were significantly associated with the serum concentration of 24 of the 35 markers examined, after adjusting for age and sex. CONCLUSIONS: Excess adiposity significantly influences circulating levels of routinely assessed laboratory markers, most notably liver enzymes, lipids/lipoproteins, inflammatory markers, and uric acid in children and adolescents. Although it is unknown whether altered biochemical marker levels in subjects with overweight/obesity reflect health or indolent disease, clinicians should be aware of the effect of weight status on several laboratory tests.