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- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 2. |
- van den Berg, Johannes, 1962-
(författare)
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Indicators and predictors of sleepiness
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sleep is a basic need as important as physical fitness and good nutrition. Without enough sleep, we will create a sleep debt and experience sleepiness. Sleepiness can be defined as the inability to stay awake, a condition that has become a health problem in our 24-hour-7-day-a-week society. Estimates suggest that up to one-third of the population suffers from excessive sleepiness. Among other interactions, sleepiness affects our performance, increasing the risk of being involved in accidents. A considerable portion of work related accidents and injuries are related to sleepiness resulting in large costs for the individuals and society. Professional drivers are one example of workers who are at risk of sleepiness related accidents. Up to 40% of heavy truck accidents could be related to sleepiness. A better knowledge about reliable indicators and predictors of sleepiness is important in preventing sleepiness related accidents.This thesis investigates both objective and subjective indicators of sleepiness, how these relate to each other, and how their pattern changes over time. The indicators investigated were electroencephalography, heart rate variability, simple reaction time, head movement, and subjective ratings of sleepiness (Study I-IV). In Study V, a questionnaire study was conducted with professional drivers in northern Sweden. This study mainly deals with predictors of sleepiness. When subjects were sleep deprived both objective and subjective ratings indicated a rapid increase in sleepiness during the first hour of the test followed by a levelling off. This change in pattern was evident for all the indicators except heart rate and heart rate variability. On the other hand, HRV was correlated with the increase of EEG parameters during the post-test sleep period. The changes in pattern of the indicators included in the thesis are analysed in the perspective of temporal patterns and relationships. Of the tested indicators, a subjective rating of sleepiness with CR-10 was considered to be the most reliable indicator of sleepiness. Of the investigated predictors of sleepiness, prior sleep habits were found to be strongly associated to sleepiness and the sleepiness related symptoms while driving. The influences of driving conditions and individual characteristics on sleepiness while driving were lower. A multidisciplinary approach when investigating and implementing indicators and predictors of sleepiness is important. In addition to their actual relations to the development of sleepiness, factors such as technical and practical limitations, work, and individual and situational needs must be taken into account.
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