The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children-Analyses based on path models.

Background: The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP.

A comparison of two collapsing methods in different approaches.

Sequencing technologies have enabled the investigation of whole genomes of many individuals in parallel. Studies have shown that the joint consideration of multiple rare variants may explain a relevant proportion of the genetic basis for disease so that grouping of rare variants, termed collapsing, can enrich the association signal. Following this assumption, we investigate the type I error and the power of two proposed collapsing methods (combined multivariate and collapsing method and the functional principal component analysis [FPCA]-based statistic) using the case-control data provided for the Genetic Analysis Workshop 18 with knowledge of the true model.

A comprehensive evaluation of collapsing methods using simulated and real data: excellent annotation of functionality and large sample sizes required.

The advent of next generation sequencing (NGS) technologies enabled the investigation of the rare variant-common disease hypothesis in unrelated individuals, even on the genome-wide level. Analysis of this hypothesis requires tailored statistical methods as single marker tests fail on rare variants. An entire class of statistical methods collapses rare variants from a genomic region of interest (ROI), thereby aggregating rare variants.

Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ.

Comparison of collapsing methods for the statistical analysis of rare variants.

Novel technologies allow sequencing of whole genomes and are considered as an emerging approach for the identification of rare disease-associated variants. Recent studies have shown that multiple rare variants can explain a particular proportion of the genetic basis for disease. Following this assumption, we compare five collapsing approaches to test for groupwise association with disease status, using simulated data provided by Genetic Analysis Workshop 17 (GAW17).

Statistical analysis of rare sequence variants: an overview of collapsing methods.

With the advent of novel sequencing technologies, interest in the identification of rare variants that influence common traits has increased rapidly. Standard statistical methods, such as the Cochrane-Armitage trend test or logistic regression, fail in this setting for the analysis of unrelated subjects because of the rareness of the variants. Recently, various alternative approaches have been proposed that circumvent the rareness problem by collapsing rare variants in a defined genetic region or sets of regions.

A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.

Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa.