Even among scientists, there is some blurring and some overlap in the usage of the words "genetics" and "genomics." In this article that looks at a slice of the interaction between these two disciplines, a distinction must be made. "Genetics" concerns the study of a single gene of known function and its effects. A genetic disease is usually one that has a single defective gene as its assigned cause and follows a classical Mendelian pattern of inheritance. Examples include cystic fibrosis, Huntington’s disease, and Tay-Sachs disease. By comparison, "genomics" refers to the study of the entire genome. The wide lens of genomics is used to capture the big picture around complex diseases such as cancer, diabetes, and asthma.
However, researchers are also using genomics to study genetic diseases, including those that may be characterized by a single mutation. These researchers have shown that genome-wide analysis can be a highly productive approach to the study of single-gene defect diseases. There are wide variations in the phenotypes of those diseases, including age of onset, disease severity, and response to treatment, and some of those variations, as it turns out, have genetic determinants.
New cystic fibrosis pathways found
Cystic fibrosis (CF) is a single-gene disorder causing multiple-organ dysfunction, frequent lung infections, and reduced life expectancy. The severity of symptoms varies widely between individuals, even those with mutations on both copies of the CFTR (cystic fibrosis transmembrane conductance regulator) gene.
Heritability studies have shown that this diversity can be associated with genetic variation occurring elsewhere in the genome. A research group composed of collaborators from Canada, France, and the United States recently published the results of a study in which they sought to identify those genetic modifiers. Combining transcriptomics and genomics, the group analyzed nasal epithelial tissue using RNA-Seq to assess expression in patients with CF at varying levels of disease severity. They then performed a genome-wide association study (GWAS) to correlate single-nucleotide polymorphism (SNP) variations with the gene expression data and identify pathways involved in determining disease progression and severity. Significance analysis of the expression data identified viral infection, inflammatory signaling, lipid metabolism, macrophage function, and innate immunity associated with disease severity. Similarly, the GWAS component identified viral response, inflammation, mucin/goblet cell binding, and cilia function associated with disease severity.
Further study of the genes composing these pathways uncovered underlying heritability of traits associated with disease severity. The authors noted that these candidate disease-severity pathways identified by gene expression and GWAS could offer novel targets for precision therapies in the management of cystic fibrosis.
DMD disease modifiers identified
Duchenne Muscular Dystrophy (DMD) is a rare, X-linked recessive disorder caused by a mutation in the gene for the dystrophin protein. Affected individuals typically lose the ability to walk by age 12. Average life expectancy is 26 years.
Symptomatic variations between individuals bearing the DMD mutation suggests the possibility that disease progression might be forestalled, if the molecular mechanisms behind those variations were known and successfully targeted. Recently, scientists from the University of Utah and The Ohio State University published an article detailing their efforts to find genes that modify the progression of DMD. The scientists had previously found that coding variants in latent transforming growth factor beta-binding protein 4 (LTBP4) were associated with prolonged ambulation. To look for additional DMD modifier genes, they performed a genome-wide association study for SNPs influencing loss of ambulation. Two loci associated with prolonged ambulation met genome-wide significance. Additional study found that one SNP tags regulatory variants of LBPT4, the gene studied previously. The other SNP tags regulatory variants of thrombospondin-1 (THBS1), an activator of TGFβ signaling by direct binding to LTBP4.
The authors concluded that regulatory variants associated with reduced expression of LTBP4 and THBS1 prolong ambulation in the cohort of DMD patients studied. They also reminded readers that genome-wide significant non-coding variants in two interacting genes were identified in a study of just 253 patients, and suggested that their genomics-based approach to genetic disease research will uncover additional modifiers when applied to larger cohorts.
Genomic analysis of fragile X yields unexpected results
Fragile X syndrome (FXS) is another genetic disease in the "single-gene defect" category. It is caused by mutations in the 5' untranslated region of the FMR1 gene. These mutations take the form of an expanded CGG triplet repeat. In normal, unaffected individuals, this triplet is repeated up to 40 times. In individuals with Fragile X syndrome, it is repeated more than 200 times.
These mutations arise spontaneously, which is why researchers from Sweden and the United States conducting a study of FXS and autism were surprised to discover multiple genome-wide significant signals near the FMR1 gene. The researchers identified five SNPs that met genome-wide significance, arranged within a 66 kb interval located 75 kb 5' of FMR1. After examining a number of potential alternative explanations for their unexpected findings, including allele assignment, control selection, sample bias and other errors, the researchers concluded that their genome-wide association study of FXS cases had in fact identified an unusually strong association with the FMR1 region.
Further, the authors noted that their finding was not previously unknown to science—microsatellite studies published 20 years previously reported linkage disequilibria between the fragile X locus and its flanking markers. Now that this finding has been replicated by GWAS, its clinical relevance should be considered. For example, to speed diagnosis while maximizing laboratory efficiency, subjects with features of FXS and a risk haplotype composed of the significant SNPs could be recommended for FMR1 CGG repeat analysis.
A salutary reminder
Genomic approaches to genetic diseases uncover vast unknown associations both near and far from the known, causal, single genes. "This is a salutary reminder of the complexity of even 'simple' monogenetic disorders," noted the authors of the fragile X paper. Newly discovered genetic features associated with disease risk and progression present new opportunities, including the potential identification of druggable targets and the development of new therapies that modify progression, forestall symptoms, or accelerate accurate diagnoses so patients can get the medical help they need sooner.