Thermo ebook on eQTL - 16

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 pathways associated with disease severity. Similarly, the
GWAS component identified viral response, inflammation, mucin/goblet cell binding, and cilia function pathways associated with disease severity.

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 noncoding 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.

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.

Genomic analysis of fragile X yields
unexpected results

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.

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.

Symptomatic variations between individuals
bearing the DMD mutation suggest 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

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

https://www.ncbi.nlm.nih.gov/pubmed/30014611

Thermo ebook on eQTL

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