👤 David Bonet

Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae. Eight hundred seventy-seven youth (6-21 years) with overweight/obesity, recruited from the Yale Pediatric Obesity Clinic in New Haven, CT, underwent genetic analysis to screen for functionally damaging, rare variants (MAF < 0.01) in MC4R. Participants were assigned to a Pathogenic Variant or No Pathogenic Variant group and completed a 10-timepoint 180-min oral glucose tolerance test (OGTT) and abdominal MRI. Compared to the No Pathogenic Variant group, the Pathogenic Variant group demonstrated significantly greater glucose concentrations (AUC Pathogenic variants in MC4R are associated with increased VAT, HFF%, and insulin resistance, independent from the degree of obesity in youth. Show less

Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in all known FH genes, together with variants in APOE, CREB3L3, and PLIN1, contribute to a molecular FH diagnosis in 67% of families, including novel gene-disruptive copy number variants (CNVs) which arose in a native American background. Second, ancestry-adjusted polygenic risk score analysis identified a significant liability for coronary artery disease, hypertension, LDL, HDL, and Type 2 Diabetes. The polygenic signal for LDL was present in patients with rare, pathogenic FH mutations and was more prominent in individuals bereft of a molecular FH diagnosis. Finally, we report both a whole-gene duplication and common, non-coding variants in a novel locus, PDZK1, which contribute to the genetic burden of FH, a finding we replicated in the UK Biobank (UKB). Together, our analyses illustrate the value of genetic studies in non-European populations and reinforce the notion that individual risk to disease can arise from both rare, large effect alleles (alone or in combination across genes) and common variants that increase the mutational burden of a biological system. Show less