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- Sliz, E., et al.
(author)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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- Tabassum, R, et al.
(author)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Journal article (peer-reviewed)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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- Kurki, MI, et al.
(author)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Journal article (peer-reviewed)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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- Orešič, Matej, 1967-, et al.
(author)
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Metabolome in progression to Alzheimer's disease
- 2011
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In: Translational Psychiatry. - New York : Nature Publishing Group. - 2158-3188. ; 1
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Journal article (peer-reviewed)abstract
- Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.
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- Julkunen, V, et al.
(author)
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Cortical thickness analysis to detect progressive mild cognitive impairment: a reference to Alzheimer's disease
- 2009
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 28:5, s. 404-412
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Journal article (peer-reviewed)abstract
- <i>Background/Aims:</i> Mild cognitive impairment (MCI) is associated with an increased risk of Alzheimer’s disease (AD). It would be advantageous to be able to distinguish the characteristics of those MCI patients with a high probability to progress to AD if one wishes to monitor the disease development and treatment. <i>Methods:</i> We assessed the baseline MRI and maximum of 7 years clinical follow-up data of 60 MCI subjects in order to examine differences in cortical thickness (CTH) between the progressive MCI (P-MCI) and stable MCI (S-MCI) subjects. CTH was measured using an automatic computational surface-based method. During the follow-up, 15 MCI subjects converted to AD on average 1.9 ± 1.3 years after the baseline examination, while 45 MCI subjects remained stable. <i>Results:</i> The P-MCI group displayed significantly reduced CTH bilaterally in the superior and middle frontal, superior, middle and inferior temporal, fusiform and parahippocampal regions as well as the cingulate and retrosplenial cortices and also in the right precuneal and paracentral regions compared to S-MCI subjects. <i>Conclusions:</i> Analysis of CTH could be used in conjunction with neuropsychological testing to identify those subjects with imminent conversion from MCI to AD several years before dementia diagnosis.
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- Nilsson, Christina, 1959, et al.
(author)
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Women-centred interventions to increase vaginal birth after caesarean section (VBAC): A systematic review
- 2015
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In: Midwifery. - : Elsevier BV. - 0266-6138 .- 1532-3099. ; 31:7, s. 657-663
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Journal article (peer-reviewed)abstract
- Objective: to evaluate the effectiveness of women centred interventions during pregnancy and birth to increase rates of vaginal birth after caesarean. Design: we searched bibliographic databases for randomised trials or cluster randomised trials on women centred interventions during pregnancy and birth designed to increase VBAC rates in women with at least one previous caesarean section. Comparator groups included standard or usual care or an alternative treatment aimed at increasing VBAC rates. The methodological quality of included studies was assessed independently by two authors using the Effective Public Health Practice Project quality assessment tool. Outcome data were extracted independently from each included study by two review authors. Findings: in total, 821 citations were identified and screened by title and abstract; 806 were excluded and full text of 15 assessed. Of these, 12 were excluded leaving three papers included in the review. Two studies evaluated the effectiveness of decision aids for mode of birth and one evaluated the effectiveness of an antenatal education programme. The findings demonstrate that neither the use of decision aids nor information/education of women have a significant effect on VBAC rates. Nevertheless, decision-aids significantly decrease women's decisional conflict about mode of birth, and information programmes significantly increase their knowledge about the risks and benefits of possible modes of birth. Key conclusions: few studies evaluated women-centred interventions designed to improve VBAC rates, and all interventions were applied in pregnancy only, none during the birth. There is an urgent need to develop and evaluate the effectiveness of all types of women-centred interventions during pregnancy and birth, designed to improve VBAC rates. Implications for practice: decision-aids and information programmes during pregnancy should be provided for women as, even though they do not affect the rate of VBAC, they decrease women's decisional conflict and increase their knowledge about possible modes of birth. (C) 2015 Elsevier Ltd. All rights reserved.
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