Genetic association of molecular traits: A help to identify causative variants in complex diseases.

In the past 15 years, major progresses have been made in the understanding of the genetic basis of regulation of gene expression. These new insights have revolutionized our approach to resolve the genetic variation underlying complex diseases. Gene transcript levels were the first expression phenotypes that were studied. They are heritable and therefore amenable to genome-wide association studies. The genetic variants that modulate them are called expression quantitative trait loci. Their study has been extended to other molecular quantitative trait loci (molQTLs) that regulate gene expression at the various levels, from chromatin state to cellular responses. Altogether, these studies have generated a wealth of basic information on the genome-wide patterns of gene expression and their inter-individual variation. Most importantly, molQTLs have become an invaluable asset in the genetic study of complex diseases. Although the identification of the disease-causing variants on the basis of their overlap with molQTLs requires caution, molQTLs can help to prioritize the relevant candidate gene(s) in the disease-associated regions and bring a functional interpretation of the associated variants, therefore, bridging the gap between genotypes and clinical phenotypes.

A functional AT/G polymorphism in the 5'-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14.

The immunoglobulin E (IgE)-associated locus on human chromosome 13q14 influencing asthma-related traits contains the genes PHF11 and SETDB2. SETDB2 is located in the same linkage disequilibrium region as PHF11 and polymorphisms within SETDB2 have been shown to associate with total serum IgE levels. In this report, we sequenced the 15 exons of SETDB2 and identified a single previously ungenotyped mutation (AT/G, rs386770867) in the 5'-untranslated region of the gene. The polymorphism was found to be significantly associated with serum IgE levels in our asthma cohort (P=0.0012). Electrophoretic mobility shift assays revealed that the transcription factor Ying Yang 1 binds to the AT allele, whereas SRY (Sex determining Region Y) binds to the G allele. Allele-specific transcription analysis (allelotyping) was performed in 35 individuals heterozygous for rs386770867 from a panel of 200 British families ascertained through probands with severe stage 3 asthma. The AT allele was found to be significantly overexpressed in these individuals (P=1.26×10(-21)). A dual-luciferase assay with the pGL3 luciferase reporter gene showed that the AT allele significantly affects transcriptional activities. Our results indicate that the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2.

Genetic linkage of progressive pseudorheumatoid dysplasia to a 3-cM interval of chromosome 6q22.

Progressive pseudorheumatoid dysplasia (PPD), MIM 208230, is an autosomal-recessive disorder, clinically characterized by spondyloepiphyseal dysplasia and progressive arthropathy. Linkage analysis of three families of different geographic and ethnic origin, including 11 affected individuals, showed strong evidence for localization of a gene for progressive pseudorheumatoid dysplasia to chromosome 6q with a maximum two-point lod score for D6S1647 of 8.34 at theta=0. Analysis of regions of homozygosity placed the gene in a 3-cM interval between D6S 1594 and D6S432. No significant shared haplotype was found for markers of the linked interval in the three families analyzed. Five genes encoding collagen and one encoding a specific procollagen-processing enzyme that map near this interval represent good candidates for the PPD gene.