Copy number variation in metabolic phenotypes

Abstract

Despite successes in identifying genetic contributors to common metabolic phenotypes, only part of the heritable component of these traits has thus far been explained. Copy number variation (CNV) is likely to be responsible for some of the unexplained variation. As observed with single nucleotide changes, it is probable that both rare and common CNVs will contribute to susceptibility to metabolic disease. For instance, CNVs in the LDLR gene underlie a substantial portion of disease in patients with heterozygous familial hypercholesterolemia. As well, a common CNV in LPA encoding apolipoprotein(a) is the primary determinant of plasma lipoprotein(a) concentrations, a risk factor for atherosclerosis. Recent efforts to map CNVs in control populations have defined their size, frequency and distribution. Many of the identified CNVs overlap genes with important functions in metabolic pathways. The overlap of CNVs that were found in control datasets with functional candidate genes or genes with previous evidence of association with metabolic syndrome presents an important subset for future CNV association studies. Finally, we describe an approach to search for CNVs in a rare high-penetrance metabolic disorder, namely lipodystrophy. As methods to identify CNVs increase in precision and accuracy, the prospect of identifying their role in both rare Mendelian and common complex metabolic phenotypes will become a reality.

Implications of gene copy-number variation in health and diseases

“…It was found that the low-density lipoprotein receptor gene (LDLR) is found to be affected in the patients with familial hypercholesterolemia. 53,54 CNV AND METABOLIC DISEASES Type 2 diabetes Type 2 diabetes is a chronic metabolic disorder characterized by high glucose level or insulin resistance. Various SNPs have been linked to the high risk for diabetes but other genetic variations such as CNV were not explored.…”

The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype

“…In addition, CNV analysis has revealed a number of additional causative mutations in the LDLR gene in patients with familial hypercholesterolemia (Reviewed by [82]). Relatively rare CNVs identified in the LPL, LIPC and LIPG genes were found to be associated with loss of enzymatic activity [83]. No association between HL and CAD has been found by GWAS.…”

Genetic causes of high and low serum HDL-cholesterol

“…Copy number variations (CNV), deletions and duplications, have gained most attention due to their generality and potential dosage effect and because they are easier to assay. Recent estimates report that about 40% of the known genes are overlapped by CNVs ( 197 ).…”

“…These fi ndings suggest that rare CNVs could also underline the HDL defi ciency cases with no known causative mutations. Likewise, a common CNV in the lipoprotein(a), kringle IV, has been shown to account for ‫ف‬ 50% of the variation in plasma lipoprotein(a) levels ( 197 ). However, as of yet, CNVs (rare and common) have not been comprehensively explored in genetic studies for lipids, mainly because of the challenges in yielding accurate genotypes ('CNV calling') required for association analysis (as opposed to the lower accuracy needed for CNV discovery) ( 201 ).…”