Genetic variants associated with sleep disorders

Abstract

Objective The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. Methods Patients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance. Results In peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep. Conclusions SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways

“…The top gene BTBD9 ( P =8.51×10 -23 ) on chromosome 6 in locus 81 was also mapped by positional and eQTL mapping (tissue type: left ventricle of the heart), and is part of a pathway regulating circadian rhythms. BTBD9 has been associated with RLS, periodic limb movement disorder 24,25 and Tourette Syndrome 26 . Involvement in sleep regulation was shown in Drosophila 27 , and mouse mutants show fragmented sleep 28 and increased levels of dynamin 1 29 , a protein that mediates the increased sleep onset latency following pre-sleep arousal 30 .…”

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

“…We also examined generalizability of previously reported AHI candidate gene results to our Hispanic/Latino cohorts (see Table E6) (23)(24)(25)(26)(27)(28)(29)(30)(31). Of 17 SNPs tested We searched for SNPs with supporting ENCODE or Roadmap Epigenomics regulatory evidence as calculated by HaploReg (33).…”

Periodontal Status in Morbidly Obese Patients With and Without Obstructive Sleep Apnea Syndrome Risk: A Cross‐Sectional Study

“…BMI is an inexact surrogate for adiposity. Indeed, individuals with a high BMI do not necessarily have a high body fat percentage 34 . Obesity is recognized as the strongest risk factor for OSAS.…”

“…Indeed, individuals with a high BMI do not necessarily have a high body fat percentage. 34 Obesity is recognized as the strongest risk factor for OSAS. In the present study, to measure obesity, other parameters besides BMI were analyzed, including NC, WC, WHR, and EPNC.…”