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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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- Rönö, K., et al.
(författare)
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The neurodevelopmental morbidity of children born after assisted reproductive technology: a Nordic register study from the Committee of Nordic Assisted Reproductive Technology and Safety group
- 2022
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 117:5, s. 1026-1037
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess the risk of neurodevelopmental disorders in singletons born after the use of assisted reproductive technology (ART) compared with singletons born without the use of ART. Design: Nordic register-based study. Setting: Cross-linked data from Medical Birth Registers and National ART and Patient Registers; liveborn singletons in 1995–2014 in Denmark and Finland, 2005–2015 in Norway, and 1995–2015 in Sweden with follow-up to 2014 (Denmark and Finland) or 2015 (Norway and Sweden). Patients: A total of 5,076,444 singletons: 116,909 (2.3%) born with and 4,959,535 (97.7%) born without the use of ART (non-ART). Interventions: In vitro fertilization, intracytoplasmic sperm injection, and fresh and frozen embryo transfer. Main Outcome Measures: The primary outcomes (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes) were learning and motor functioning disorders (F80–F83), autism spectrum disorder (F84), attention-deficit/hyperactivity disorder and conduct disorders (F90–F92), and tic disorders (F95). Crude hazard ratios (HRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals were calculated. Results: Singletons in the ART cohort had a higher adjusted risk of learning and motor functioning disorders (HR, 1.01 [0.96–1.07]; aHR, 1.17 [1.11–1.24]) and a tendency toward a higher risk of autism spectrum disorder (HR, 1.12 [1.04–1.21]; aHR, 1.07 [0.98–1.16]) and attention-deficit/hyperactivity disorder and conduct disorders (HR, 0.82 [0.77–0.86]; aHR, 1.17 [0.99–1.12]) but not of tic disorders (HR, 1.21 [1.06–1.38]; aHR, 1.17 [0.96–1.27]). No differences in risk were found between children born after in vitro fertilization and intracytoplasmic sperm injection or after fresh and frozen embryo transfer. Conclusions: Our findings of only small differences in neurodevelopment between ART and non-ART singletons are reassuring and in line with previous studies. © 2022 American Society for Reproductive Medicine
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3. |
- Watts, Eleanor L., et al.
(författare)
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Circulating free testosterone and risk of aggressive prostate cancer : Prospective and Mendelian randomisation analyses in international consortia
- 2022
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 151:7, s. 1033-1046
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.
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