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- van Rheenen, Wouter, et al.
(author)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Journal article (peer-reviewed)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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- Morrison, S. A., et al.
(author)
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Bed rest and hypoxic exposure affect sleep architecture and breathing stability
- 2017
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In: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 8:June
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Journal article (peer-reviewed)abstract
- Objective: Despite over 50 years of research on the physiological effects of sustained bed rest, data characterizing its effects on sleep macrostructure and breathing stability in humans are scarce. This study was conducted to determine the effects of continuous exposure to hypoxia and sustained best rest, both individually and combined, on nocturnal sleep and breathing stability. Methods: Eleven participants completed three randomized, counter-balanced, 21-days trials of: (1) normoxic bed rest (NBR, PIO2 = 133.1 ± 0.3), (2) hypoxic ambulatory confinement (HAMB, PIO2 = 90.0 ± 0.4) and (3) hypoxic bed rest (HBR, PIO2 = 90.0 ± 0.4; ~4,000 m equivalent altitude). Full objective polysomnography was performed at baseline, on Night 1 and Night 21 in each condition. Results: In NBR Night 1, more time was spent in light sleep (10 ± 2%) compared to baseline (8 ± 2%; p = 0.028); Slow-wave sleep (SWS) was reduced from baseline in the hypoxic-only trial by 18% (HAMB Night 21, p = 0.028) and further reduced by 33% (HBR Night 1, p = 0.010), and 36% (HBR Night 21, p = 0.008) when combined with bed rest. The apnea-hypopnea index doubled from Night 1 to Night 21 in HBR (32-62 events·h-1) and HAMB (31-59 events·h-1; p = 0.002). Those who experienced greatest breathing instability from Night 1 to Night 21 (NBR) were correlated to unchanged or higher (+1%) night SpO2 concentrations (R2 = 0.471, p = 0.020). Conclusion: Bed rest negatively affects sleep macrostructure, increases the apnea-hypopnea index, and worsens breathing stability, each independently exacerbated by continuous exposure to hypoxia.
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- Tellez, H.F., et al.
(author)
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eAMI : A Qualitative Quantification of Periodic Breathing Based on Amplitude of Oscillations
- 2015
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In: Sleep. - : Oxford University Press (OUP). - 0161-8105 .- 1550-9109. ; 38:3, s. 381-389
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Journal article (peer-reviewed)abstract
- Study Objectives:Periodic breathing is sleep disordered breathing characterized by instability in the respiratory pattern that exhibits an oscillatory behavior. Periodic breathing is associated with increased mortality, and it is observed in a variety of situations, such as acute hypoxia, chronic heart failure, and damage to respiratory centers. The standard quantification for the diagnosis of sleep related breathing disorders is the apnea-hypopnea index (AHI), which measures the proportion of apneic/ hypopneic events during polysomnography. Determining the AHI is labor-intensive and requires the simultaneous recording of airflow and oxygen saturation. In this paper, we propose an automated, simple, and novel methodology for the detection and qualification of periodic breathing: the estimated amplitude modulation index (eAMI).Patients or Participants:Antarctic Cohort (3800 meters): 13 normal individuals. Sleep Clinic Cohort: 39 different patients suffering from diverse sleep-related pathologies.Measurements and Results:When tested in a population with high levels of periodic breathing (Antarctic Cohort), eAMI was closely correlated with AHI (r = 0.95, P < 0.001). When tested in the clinical setting, the proposed method was able to detect portions of the signal in which subclinical periodic breathing was validated by an expert (n = 93; accuracy = 0.85). Average eAMI was also correlated with the loop gain for the combined clinical and Antarctica cohorts (r = 0.58, P < 0.001).Conclusions:In terms of quantification and temporal resolution, the eAMI is able to estimate the strength of periodic breathing and the underlying loop gain at any given time within a record. The impaired prognosis associated with periodic breathing makes its automated detection and early diagnosis of clinical relevance.
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