ARTICLE: Genome-Wide Association Studies in Obstructive Sleep Apnea. Will We Catch a Black Cat in a Dark Room?

AUTHORS: Luu V. Pham and Vsevolod Y. Polotsky

JOURNAL: Am J Respir Crit Care Med. 2016 Oct 1;194(7):789-791.

Giant strides have been made during the last 3 decades in deciphering genetics of rare diseases such as cystic fibrosis or Huntington disease. These strides were based on linkage analysis in families affected by a rare disease, using genetic markers across the genome. However, the linkage analysis uniformly failed in complex diseases such as cancer, cardiovascular diseases, and obstructive sleep apnea.

The common disease–common variant hypothesis (1) argues that genetic susceptibility to common disease is a result of variations in the genome that occur at high frequency in the population, but have small effects on disease expression. Genome-wide association studies (GWASs) seek associations between common gene variants, usually single-nucleotide polymorphism (SNPs), and specific diseases. The first successful GWAS published in 2005 identified a common variant in the complement factor H gene as a potential cause of age-related macular degeneration (2). During the subsequent 8 years, thousands of SNPs were identified in nearly 2,000 published human GWASs (3), resulting in significant progress in understanding diabetes, obesity, and other highly prevalent complex diseases.

The GWAS design has been applied to rare and common sleep disorders. Studies in narcolepsy and restless leg syndrome identified genes conferring susceptibility and contributing to the pathogenesis of these disorders (46). In contrast to restless leg syndrome and narcolepsy, sleep disordered breathing (SDB) is a heterogeneous and complex disease. Multiple mechanisms including upper airway structural properties and neuromuscular control, ventilatory control, and sleep–wake regulation influence the overall expression of the disease (7). Nongenetic factors including obesity, age, and comorbid cardiopulmonary disease can significantly affect susceptibility to SDB. Moreover, SDB severity is multidimensional and can be characterized by type, frequency, and duration of apneic events; severity of gas exchange abnormalities; and presence of arousals. Given the complexity of SDB, prerequisites for a definitive genetics study would be a large number of research subjects and clearly defined phenotypes. Nevertheless, previous studies in the genetics of SDB were limited by small sample sizes and the reduction of SDB dimensions to the AHI (89).

In this issue of the Journal, Cade and colleagues (pp. 886–897) present the first genome-wide SDB study that yielded SNPs reaching acceptable levels of significance (10). Furthermore, the results were independent of body mass index. The authors employed two methods to overcome limitations of existing studies in SDB genetics. First, they achieved a large sample size by pooling data from three separate cohorts. Second, in addition to the traditional apnea–hypopnea index, the authors defined SDB phenotypes by mean nocturnal oxyhemoglobin saturation and mean event duration. The apnea–hypopnea index was associated with a SNP in proximity of the GPR83 gene. GPR83 is expressed in the areas of the brain involved in upper airway neuromuscular and respiratory control, including hypoglossal nucleus, dorsal motor nucleus of vagus, and the nucleus of the solitary tract. GPR83 appears to be involved in regulation of metabolic rate and immune responses. Nevertheless, significance of this finding may be diminished by the opposite effect of this SNP on the apnea–hypopnea index in two pooled cohorts: MESA (the Multi-Ethnic Study of Atherosclerosis) and HCHS/SOL (Hispanic Community Health Study/Study of Latinos).

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