GEIRA: gene-environment and gene–gene interaction research application

The GEIRA (Gene-Environment and Gene–Gene Interaction Research Application) algorithm and subsequent program is dedicated to genome-wide gene-environment and gene–gene interaction analysis. It implements concepts of both additive and multiplicative interaction as well as calculations based on dominant, recessive and co-dominant genetic models, respectively. Estimates of interactions are incorporated in a single table to make the output easily read. The algorithm is coded in both SAS and R. GEIRA is freely available to non-commercial users at http://www.epinet.se. Additional information, including user’s manual and example datasets is available online at http://www.epinet.se

Long working hours and risk of 50 health conditions and mortality outcomes : a multicohort study in four European countries

Background: Studies on the association between long working hours and health have captured only a narrow range of outcomes (mainly cardiometabolic diseases and depression) and no outcome-wide studies on this topic are available. To achieve wider scope of potential harm, we examined long working hours as a risk factor for a wide range of disease and mortality endpoints. Methods: The data of this multicohort study were from two population cohorts from Finland (primary analysis, n=59 599) and nine cohorts (replication analysis, n=44 262) from Sweden, Denmark, and the UK, all part of the Individual-participant Meta-analysis in Working Populations (IPD-Work) consortium. Baseline assessed long working hours (>55 hours per week) were compared to standard working hours (35-40 h). Outcome measures with follow-up until age 65 years were 46 diseases that required hospital treatment or continuous pharmacotherapy, all-cause, and three cause-specific mortality endpoints, ascertained via linkage to national health and mortality registers. Findings: 2747 (4.6%) participants in the primary cohorts and 3027 (6.8%) in the replication cohorts worked long hours. After adjustment for age, sex, and socioeconomic status, working long hours was associated with increased risk of cardiovascular death (hazard ratio 1.68; 95% confidence interval 1.08-2.61 in primary analysis and 1.52; 0.90-2.58 in replication analysis), infections (1.37; 1.13-1.67 and 1.45; 1.13-1.87), diabetes (1.18; 1.01-1.38 and 1.41; 0.98-2.02), injuries (1.22; 1.00-1.50 and 1.18; 0.98-1.18) and musculoskeletal disorders (1.15; 1.06-1.26 and 1.13; 1.00-1.27). Working long hours was not associated with all-cause mortality. Interpretation: Follow-up of 50 health outcomes in four European countries suggests that working long hours is associated with an elevated risk of early cardiovascular death and hospital-treated infections before age 65. Associations, albeit weak, were also observed with diabetes, musculoskeletal disorders and injuries. In these data working long hours was not related to elevated overall mortality. (C) 2021 The Authors. Published by Elsevier Ltd.Peer reviewe

Job Strain as a Risk Factor for Peripheral Artery Disease : A Multi-Cohort Study

Background Job strain is implicated in many atherosclerotic diseases, but its role in peripheral artery disease (PAD) is unclear. We investigated the association of job strain with hospital records of PAD, using individual-level data from 11 prospective cohort studies from Finland, Sweden, Denmark, and the United Kingdom. Methods and Results Job strain (high demands and low control at work) was self-reported at baseline (1985-2008). PAD records were ascertained from national hospitalization data. We used Cox regression to examine the associations of job strain with PAD in each study, and combined the study-specific estimates in random effects meta-analyses. We used tau(2), I-2, and subgroup analyses to examine heterogeneity. Of the 139 132 participants with no previous hospitalization with PAD, 32 489 (23.4%) reported job strain at baseline. During 1 718 132 person-years at risk (mean follow-up 12.8 years), 667 individuals had a hospital record of PAD (3.88 per 10 000 person-years). Job strain was associated with a 1.41-fold (95% CI, 1.11-1.80) increased average risk of hospitalization with PAD. The study-specific estimates were moderately heterogeneous (tau(2)=0.0427, I-2: 26.9%). Despite variation in their magnitude, the estimates were consistent in both sexes, across the socioeconomic hierarchy and by baseline smoking status. Additional adjustment for baseline diabetes mellitus did not change the direction or magnitude of the observed associations. Conclusions Job strain was associated with small but consistent increase in the risk of hospitalization with PAD, with the relative risks on par with those for coronary heart disease and ischemic stroke.Peer reviewe

A genome-wide association scan on estrogen receptor-negative breast cancer

Introduction: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.Methods: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.Results: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer share

Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women

Peer reviewe

The genetic history of Scandinavia from the Roman Iron Age to the present

The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. We used resources from projects SNIC 2022/23-132, SNIC 2022/22-117, SNIC 2022/23-163, SNIC 2022/22-299, and SNIC 2021-2-17. This research was supported by the Swedish Research Council project ID 2019-00849_VR and ATLAS (Riksbankens Jubileumsfond). Part of the modern dataset was supported by a research grant from Science Foundation Ireland (SFI), grant number 16/RC/3948, and co-funded under the European Regional Development Fund and by FutureNeuro industry partners.Peer reviewedPublisher PD

Effort-Reward Imbalance at Work and Incident Coronary Heart Disease: A Multicohort Study of 90,164 Individuals.

BACKGROUND: Epidemiologic evidence for work stress as a risk factor for coronary heart disease is mostly based on a single measure of stressful work known as job strain, a combination of high demands and low job control. We examined whether a complementary stress measure that assesses an imbalance between efforts spent at work and rewards received predicted coronary heart disease. METHODS: This multicohort study (the "IPD-Work" consortium) was based on harmonized individual-level data from 11 European prospective cohort studies. Stressful work in 90,164 men and women without coronary heart disease at baseline was assessed by validated effort-reward imbalance and job strain questionnaires. We defined incident coronary heart disease as the first nonfatal myocardial infarction or coronary death. Study-specific estimates were pooled by random effects meta-analysis. RESULTS: At baseline, 31.7% of study members reported effort-reward imbalance at work and 15.9% reported job strain. During a mean follow-up of 9.8 years, 1,078 coronary events were recorded. After adjustment for potential confounders, a hazard ratio of 1.16 (95% confidence interval, 1.00-1.35) was observed for effort-reward imbalance compared with no imbalance. The hazard ratio was 1.16 (1.01-1.34) for having either effort-reward imbalance or job strain and 1.41 (1.12-1.76) for having both these stressors compared to having neither effort-reward imbalance nor job strain. CONCLUSIONS: Individuals with effort-reward imbalance at work have an increased risk of coronary heart disease, and this appears to be independent of job strain experienced. These findings support expanding focus beyond just job strain in future research on work stress