| 1. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 2. |
- Erzurumluoglu, A. Mesut, et al.
(författare)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Tidskriftsartikel (refereegranskat)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 3. |
- Varga, Tibor V., et al.
(författare)
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Association is not prediction : A landscape of confused reporting in diabetes – A systematic review
- 2020
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227. ; 170
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Appropriate analysis of big data is fundamental to precision medicine. While statistical analyses often uncover numerous associations, associations themselves do not convey predictive value. Confusion between association and prediction harms clinicians, scientists, and ultimately, the patients. We analyzed published papers in the field of diabetes that refer to “prediction” in their titles. We assessed whether these articles report metrics relevant to prediction. Methods: A systematic search was undertaken using NCBI PubMed. Articles with the terms “diabetes” and “prediction” were selected. All abstracts of original research articles, within the field of diabetes epidemiology, were searched for metrics pertaining to predictive statistics. Simulated data was generated to visually convey the differences between association and prediction. Results: The search-term yielded 2,182 results. After discarding non-relevant articles, 1,910 abstracts were evaluated. Of these, 39% (n = 745) reported metrics of predictive statistics, while 61% (n = 1,165) did not. The top reported metrics of prediction were ROC AUC, sensitivity and specificity. Using the simulated data, we demonstrated that biomarkers with large effect sizes and low P values can still offer poor discriminative utility. Conclusions: We demonstrate a landscape of confused reporting within the field of diabetes epidemiology where the term “prediction” is often incorrectly used to refer to association statistics. We propose guidelines for future reporting, and two major routes forward in terms of main analytic procedures and research goals: the explanatory route, which contributes to precision medicine, and the prediction route which contributes to personalized medicine.
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| 4. |
- Varga, Tibor V, et al.
(författare)
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Lipidomic profiles, lipid trajectories and clinical biomarkers in female elite endurance athletes
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- We assessed whether blood lipid metabolites and their changes associate with various cardiometabolic, endocrine, bone- and energy-related comorbidities of Relative Energy Deficiency in Sport (RED-S) in female elite endurance athletes. Thirty-eight Scandinavian female elite athletes underwent a day-long exercise test. Five blood samples were obtained during the day - at fasting state and before and after two standardized exercise tests. Clinical biomarkers were assessed at fasting state, while untargeted lipidomics was undertaken using all blood samples. Linear and logistic regression was used to assess associations between lipidomic features and clinical biomarkers. Overrepresentations of findings with P < 0.05 from these association tests were assessed using Fisher's exact tests. Self-organizing maps and a trajectory clustering algorithm were utilized to identify informative clusters in the population. Twenty associations PFDR < 0.05 were detected between lipidomic features and clinical biomarkers. Notably, cortisol demonstrated an overrepresentation of associations with P < 0.05 compared to other traits (PFisher = 1.9×10-14). Mean lipid trajectories were created for 201 named features for the cohort and subsequently by stratifying participants by their energy availability and menstrual dysfunction status. This exploratory analysis of lipid trajectories indicates that participants with menstrual dysfunction might have decreased adaptive response to exercise interventions.
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| 5. |
- Zheng, Yan, et al.
(författare)
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Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood
- 2020
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 35:7, s. 685-697
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = − 0.76, 95% CI − 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = − 0.06, 95% CI − 0.93 to 0.87 mmHg), or pulse pressure (β = − 0.65, 95% CI − 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses. © 2020, Springer Nature B.V.
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