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Zotcheva, E., Bergh, S., Selbaek, G., Krokstad, S., Haberg, A. K., Strand, B. H., et al. (2018). Midlife Physical Activity, Psychological Distress, and Dementia Risk: The HUNT Study. J Alzheimers Dis, 66(2), 825–833.
Abstract: BACKGROUND: Physical activity (PA) is associated with a decreased dementia risk, whereas psychological distress (distress) is linked to an increased dementia risk. OBJECTIVE: We investigated independent and joint associations of midlife moderate-to-vigorous PA (MVPA) and distress with incident dementia. METHODS: Our study comprised 28,916 participants aged 30-60 years from the Nord-Trondelag Health Study (HUNT1, 1984-1986). Data on MVPA and distress from HUNT1 was linked to the Health and Memory Study in Nord-Trondelag for dementia case identification. Participants were followed from 1995 until 2011. We used adjusted Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). RESULTS: In fully adjusted analyses, MVPA was associated with a reduced dementia risk (HR 0.81, 95% CI 0.62-1.06), compared to no MVPA. Distress was associated with an increased dementia risk (HR 1.30, 95% CI 0.99-1.70). Compared to distressed participants not taking part in MVPA, non-distressed no-MVPA participants had a reduced dementia risk (HR 0.72, 95% CI 0.54-0.96). The same applied to distressed MVPA participants (HR 0.50, 95% CI 0.22-1.14), and non-distressed MVPA participants (HR 0.63, 95% CI 0.44-0.90). Our results indicated an additive interaction between MVPA and distress on dementia risk. CONCLUSION: Our results suggest that midlife MVPA reduces risk of incident dementia among both distressed and non-distressed individuals.
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Zhou, W., Nielsen, J. B., Fritsche, L. G., Dey, R., Gabrielsen, M. E., Wolford, B. N., et al. (2018). Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet, 50(9), 1335–1341.
Abstract: In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.
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Zadro, J. R., Nilsen, T. I. L., Shirley, D., Amorim, A. B., Ferreira, P. H., & Mork, P. J. (2018). Parental chronic widespread pain and the association with chronic widespread pain in adult offspring: Family-linkage data from the Norwegian HUNT Study. Eur J Pain, .
Abstract: BACKGROUND: Individuals experiencing chronic widespread pain (CWP) have greater disability and poorer quality of life compared to those with other chronic painful conditions; although research identifying risk factors for CWP is lacking. We aimed to investigate whether parental CWP increases the risk of offspring CWP, and if offspring body mass index (BMI) and leisure time physical activity modify this association. METHODS: We included 6589 parent-offspring trios participating in the Norwegian HUNT Study in 1995-1997 and 2006-2008. Logistic regression was used to calculate adjusted odd ratios (ORs) (95% confidence intervals, CIs) as estimates of relative risk for offspring CWP. We analysed the joint effect of parental CWP and offspring BMI or leisure time physical activity on offspring risk of CWP and calculated the relative excess risk due to interaction (RERI). RESULTS: In total, 886 (13.5%) offspring developed CWP during follow-up. Having one (OR = 1.23, 95% CI, 1.05-1.44) or both parents with CWP (OR = 1.89, 95% CI, 1.50-2.38) increased the risk of offspring CWP. In analyses of joint effects, ORs were 1.84 (95% CI, 1.31-2.56) and 3.35 (95% CI, 1.94-5.77) in normal weight and obese offspring, respectively, when both parents had CWP. The estimate of RERI suggested some synergistic effect (RERI = 1.19, 95% CI, -0.68 to 3.05), although precision was low. Risk of CWP was similar in active (OR = 2.05, 95% CI, 1.56-2.70) and inactive (OR = 1.96, 95% CI, 1.31-2.91) offspring when both parents had CWP. CONCLUSION: Parental CWP increases the risk of CWP in adult offspring, particularly if both parents have CWP and offspring are obese. This highlights a familial predisposition for CWP and an important target group for preventive measures. SIGNIFICANCE: The parent-offspring transmission of CWP is stronger in obese offspring (particularly when both parents have CWP). This study is the first to investigate the interaction between modifiable lifestyle factors, familial factors and CWP.
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Xie, S. - H., Ness-Jensen, E., Medefelt, N., & Lagergren, J. (2018). Assessing the feasibility of targeted screening for esophageal adenocarcinoma based on individual risk assessment in a population-based cohort study in Norway (The HUNT Study). Am J Gastroenterol, 113(6), 829–835.
Abstract: OBJECTIVES: Unselected screening for oesophageal adenocarcinoma (OAC) is not justified due to the low absolute risk in the general population. This study aimed to evaluate a risk prediction model in identifying high-risk individuals who might be considered for targeted screening. METHODS: A population-based cohort of 62,576 participants was recruited in 1995-1997 in Nord-Trondelag County, Norway (HUNT) and followed up until 31 December 2015. A model for predicting individuals' absolute risk of OAC was developed using competing-risk regression. The Lorenz curve was used to assess the concentration of OAC patients in high-risk individuals and the feasibility of targeted screening based on individual risk assessment. RESULTS: During 1,085,137 person-years of follow-up, 29 incident cases of OAC occurred. The model included risk factors for OAC, in which male sex, older age, gastro-oesophageal reflux symptoms, obesity, and tobacco smoking predicted higher risk of OAC. The area under the receiver operating characteristic curve for 10-year risk of OAC was 0.71 (95% confidence interval 0.57-0.85) and for 15-year risk was 0.84 (95% confidence interval 0.76-0.91) after 10-fold cross-validation, with good agreements between observed and predicted risks. The Lorenz curve indicated that 33% of all OAC cases would have occurred in the 5% of the population with the highest risks within 15 years, and 61% of all cases in the top 10% of the population. CONCLUSIONS: Individual risk assessment based on known risk factors for OAC has the potential to identify a selected high-risk group of individuals who may benefit from screening for early detection.
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Winsvold, B. S., Palta, P., Eising, E., Page, C. M., van den Maagdenberg, A. M., Palotie, A., et al. (2018). Epigenetic DNA methylation changes associated with headache chronification: A retrospective case-control study. Cephalalgia, 38(2), 312–322.
Abstract: Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.
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