Estimates of heritability for asthma sufferers would suggest that nearly half of the variation in risk can be attributed to some type of genetic factor. However, common genetic variants that have been identified by genome-wide association studies (GWAS) encapsulate little of the genetic risk.

This phenomenon, known as missing heritability, is the focus of new research from scientists at the University of Chicago Medical Center published online today under the title, “Rare mutations do not explain 'missing heritability' in asthma” in Nature Communications.

Asthma affects greater than 25 million adults and children in the US. While most studies have often focused on the commonly occurring genetic mutations, the so-called genetic variants, and many have been identified, represent only a small portion of the probability to inherit or develop asthma.

“Previous studies have likely overestimated the heritability of asthma,” says Carole Ober, Ph.D., Blum-Riese Professor and chair of the department of human genetics at the University of Chicago and senior author on the paper. “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.”

Dr. Ober’s team evaluated approximately 33,000 rare or low frequency mutations from more than 11,000 individuals of diverse ethnicities representing European, African, and Latino backgrounds. They found that only mutations in the genes MTHFR, GSDMB and GRASP had any statistical link to asthma. MTHFR mutations were found primarily in individuals of African descent, while GSDMB and GRASP mutations were observed in Latino individuals.

Since these genes are involved in Vitamin B9 metabolism, regulation of apoptotic mechanisms, and protein scaffolding and have no known role in asthma, it is unlikely they account for the widespread pervasiveness of the disease. “Even if we discovered only half of all truly associated variants, it is unlikely that rare and low-frequency variants will account for a significant portion of the heritability of asthma”, wrote the scientists.

Despite the possibility that these rare mutations may not confer much risk for asthma to the population, they may serve as starting templates for drug development. Dr. Ober optimistically pointed to the development of statin drugs in the treatment of high cholesterol after the discovery of rare mutations in the LDL receptor.

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