Intermediate phenotypes of childhood obstructive sleep apnea.

An intermediate phenotype of a disease is a trait in the path of pathogenesis from genetic predisposition to disease manifestation. Identifying intermediate phenotypes with high heritability is helpful in delineating the genetics of a disorder. In this study, we aimed to examine various traits with regards to obesity, cardiovascular risk and upper airway structure to identify potential intermediate phenotypes of childhood obstructive sleep apnea (OSA). Children aged between 6 and 18 years and their parents and siblings were recruited. All subjects underwent anthropometric measurements, cardiovascular risk assessment, sonographic measurement of lateral parapharyngeal wall (LPW) thickness, X-ray cephalometry and overnight polysomnography. A total of 34 phenotypes were examined. One hundred and one families consisting of 127 children (46 overweight) and 198 adults (84 overweight) were recruited. Heritability of obstructive apnea-hypopnea index (OAHI) was significant in overweight (h2  = 0.54) but not normal-weight individuals (h2  = 0.12). LPW thickness (h2  = 0.68) and resting blood pressure (h2  = 0.36 and 0.43 for systolic blood pressure [SBP] and diastolic blood pressure [DBP], respectively) were significantly heritable and associated with OAHI. Moreover, these traits were found to have shared genetic variance with OAHI in the overweight subgroup. Hyoid bone position also had significant heritability (h2  = 0.55) and association with OAHI but genetic correlation with OSA severity was not demonstrated. These findings suggest that LPW thickness and resting blood pressure are possible intermediate phenotypes of OSA independent of body mass index, especially in overweight patients. Identifying genes relevant to these phenotypes may help to elucidate the genetic susceptibility of OSA.