University of Chicago. US: Largest study to date of rare genetic variants and asthma risk finds few associations. Despite a strong suspected link between genetics and asthma, commonly
found genetic mutations account for only a small part of the risk for
developing the disease -- a problem known as missing heritability.
Rare and low frequency genetic mutations have been thought to explain
missing heritability, but it appears they are unlikely to play a major
role, according to a new study led by scientists from the University of
Chicago. Analyzing the coding regions of genomes of more than 11,000
individuals, they identified mutations in just three genes that were
associated with asthma risk. Each was associated with risk in specific
ethnicities. Their findings, published in Nature Communications on Jan. 16, suggest gaps in the current understanding of asthma genetics.
"Previous studies have likely overestimated the heritability of
asthma," said study senior author Carole Ober, PhD, Blum-Riese Professor
and chair of the Department of Human Genetics at the University of
Chicago. "This could be because those estimates are based on
correlations between family members that share environment as well as
genes, which could inflate the heritability. Gene-environment
interactions are not considered in these large scale association
studies, and we know that these are particularly important in
establishing individual risks for asthma."
Asthma affects more than 25 million adults and children of all ages
and ethnicities in the US. Due to the widespread nature of the disease,
most studies of its genetic underpinnings have focused on commonly
occurring mutations, referred to as genetic variants. However, while
numerous such variants have been identified, they are able to account
for only a small proportion of the risk for inheriting or developing
asthma. Rare mutations, found in less than five percent of the
population, have been hypothesized to explain this disparity.
Graduate student Catherine Igartua led the analysis under the
supervision of co-senior author Dan Nicolae, PhD, Professor in the
Departments of Medicine, Statistics and Human Genetics. She evaluated
nearly 33,000 rare or low frequency mutations in more than 11,000
individuals of a variety of ethnicities representing European, African
and Latino backgrounds. She analyzed mutations jointly across subjects,
using a technique that allowed them to study mutations common in one
ethnicity, but rare in others.
Only mutations in the genes GRASP, GSDMB and MTHFR showed a
statistical link to asthma risk. Mutations in the first two genes were
found primarily in Latino individuals, and mutations in the last gene in
those with African ancestry. These genes, involved in protein
scaffolding, apoptosis regulation and vitamin B9 metabolism
respectively, have as yet unknown roles in asthma. The rarity and
ethnic-specificity of these genes is insufficient to account for the
widespread prevalence of asthma.
Although rare mutations might not contribute much to population
asthma risk, these genes still have the potential to serve as targets
for therapeutic development. Ober points to the discovery of rare
mutations in the LDL receptor that eventually led to the development of
statins to treat high cholesterol. She also notes that it is possible,
but unlikely, that there are mutations with large effects on asthma risk
outside of their screen as it looked at approximate 60 percent of
mutations in coding regions of the genome.
"It was assumed that there would be rare mutations with larger effect
sizes than the common variants we have been studying," Ober said.
"Surprisingly, we found that low frequency mutations explain only a very
small amount of asthma risk."