Genetic factors in sleep-disordered breathing

Sleep-disordered breathing (SDB) is characterized by repetitive episodes of decreased or arrested respiratory airflow during sleep. SDB is common and affects approximately 20% of the Japanese general population. Most traits of normal sleep and SDB show familial aggregation, suggesting significant effects of genetic factors. Obstructive sleep apnea (OSA) is the most common type of SDB and has a high heritability. Regardless of high heritability, no risk locus for OSA has reached a genome-wide level of significance (P < 5×10−8) in linkage or candidate gene analysis. However, a recent genome-wide association study identified some genetic risks for OSA with P < 5×10−8 for the first time. The identified genes are associated with inflammation, hypoxia signaling, and sleep pathways. The effects of genetic factors on the consequences of OSA has not been determined, although a correlation between OSA and cardiovascular disease may differ across races. Congenital central hypoventilation syndrome (CCHS) is a genetically inherited disorder caused by mutations in the paired-like homeobox 2B (PHOX2B) gene of polyalanine repeat mutations in the 20-alanine repeat or non-polyalanine repeat mutations. PHOX2B genotypes are also associated with clinical phenotypes of CCHS, including severity of hypoventilation. SDB, including obesity hypoventilation syndrome, is often seen in genetic obesity-associated disorders such as Prader-Willi syndrome. Although advances in genetics have resulted in identification of some genetic causes of SDB, further studies are required to elucidate the cellular and molecular mechanisms between genetic risks and clinical manifestations.