👤 E Schernhammer

Shift work is widespread due to 24-h work in many occupations. Understanding differences in individual shift work tolerance (SWT) can help develop coping strategies for shift workers. This in-depth qualitative review elucidates the architecture of SWT, providing an overview of the research advances in the last decade (2011-2021). We searched Google Scholar, PubMed and Medline for different word combinations concerning SWT. Genome-wide association studies (GWAS) for the potential genetic basis of SWT were additionally searched in GWAS Central and GWAS Catalogue. Eleven new studies were published since 2011, with the proportion of longitudinal studies on SWT having more than doubled in the past decade. They consolidate prior findings (e.g. hardiness most consistently associated with SWT) and discovered additional aspects of SWT like resistance to change and job stress. The 15 large-scale GWAS identified, most of which using UK Biobank (UKB) and 23andMe data, involved mapped genes showing overlap especially within analysis of the same phenotype (e.g. PER2/3 for morningness, PAX8 for sleep duration and LINGO1 for neuroticism). Individual GWAS for additional traits such as resilience have also been published though assessments of gene overlap are not yet possible. Progress regarding longitudinal studies on SWT has been made though a more consistent definition of SWT remains crucial for future research. Non-genetic studies on SWT suggest several important traits and factors; many of which have now also been explored using GWAS. Such evidence could serve as basis for individualized risk prediction and disease prevention approaches for night-shift workers. Show less

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations. Show less