| Summary: | Obstructive sleep apnea (OSA) is a common complex trait with many potential contributing factors. It is characterized by pauses in breathing during sleep due to obstruction in the upper airway. OSA is more common in men than women and in the middle-aged population. Previous studies have showed familial aggregation, but no significant association of sequence variants with OSA has been reported. The aims of the study were to assess familial aggregation of OSA in Iceland, to identify chromosomal regions/loci and genes that are linked with OSA, to analyse the effects of obesity-linked variants on the risk of OSA and to validate sequence variants in genes with suggestive association with OSA. The approaches used include analysis of familiality using a nationwide genealogy database, whole genome linkage scan in Icelandic OSA families and case-control association analyses of selected sequence variants. We showed that relatives of OSA patients are more likely to have OSA than individuals in the general population, where the first-degree relatives have more than a twofold relative risk (RR for all OSA=2.33). It was also shown that obesity adds to the risk of OSA, which was threefold for first-degree relatives of obese OSA patients. No genome wide significant linkage (a LOD score >3.7) to any chromosomal regions was observed for the OSA phenotypes tested. To finemap the suggestive linkage regions, SNPs under 10 linkage peaks with LOD scores ≥1.5 were tested for association in the corresponding OSA phenotypes and a significant association of one variant at 11p13 (P=1.26x10-6, OR=1.30 for obese OSA patients with severe, moderate or mild disease) was observed. However, when tested in additional OSA samples from Iceland and the USA the association was not replicated. Various previously published variants known to associate with obesity-related traits were tested for association with OSA in Iceland and two significant associations were found. Firstly, a variant in the FTO gene at 16q12 associated with OSA (P=0.0009, ...
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