| 1. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
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Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
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Tidskriftsartikel (refereegranskat)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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| 2. |
- Skotte, Line, et al.
(författare)
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Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:2, s. 555-568
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Tidskriftsartikel (refereegranskat)abstract
- Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
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| 3. |
- Lundgaard, Agnete T., et al.
(författare)
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BALDR : A Web-based platform for informed comparison and prioritization of biomarker candidates for type 2 diabetes mellitus
- 2023
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Ingår i: PLoS Computational Biology. - 1553-734X. ; 19:8 August
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Tidskriftsartikel (refereegranskat)abstract
- Novel biomarkers are key to addressing the ongoing pandemic of type 2 diabetes mellitus. While new technologies have improved the potential of identifying such biomarkers, at the same time there is an increasing need for informed prioritization to ensure efficient downstream verification. We have built BALDR, an automated pipeline for biomarker comparison and prioritization in the context of diabetes. BALDR includes protein, gene, and disease data from major public repositories, text-mining data, and human and mouse experimental data from the IMI2 RHAPSODY consortium. These data are provided as easy-to-read figures and tables enabling direct comparison of up to 20 biomarker candidates for diabetes through the public website https://baldr.cpr.ku.dk.
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| 4. |
- Niss, Kristoffer, et al.
(författare)
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Effects of active farnesoid X receptor on GLUTag enteroendocrine L cells
- 2020
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 517
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Tidskriftsartikel (refereegranskat)abstract
- Activated transcription factor (TF) farnesoid X receptor (FXR) represses glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine L cells. This, in turn, reduces insulin secretion, which is triggered when β cells bind GLP-1. Preventing FXR activation could boost GLP-1 production and insulin secretion. Yet, FXR's broader role in L cell biology still lacks understanding. Here, we show that FXR is a multifaceted TF in L cells using proteomics and gene expression data generated on GLUTag L cells. Most striking, 252 proteins regulated upon glucose stimulation have their abundances neutralized upon FXR activation. Mitochondrial repression or glucose import block are likely mechanisms of this. Further, FXR physically targets bile acid metabolism proteins, growth factors and other TFs, regulates ChREBP, while extensive text-mining found 30 FXR-regulated proteins to be well-known in L cell biology. Taken together, this outlines FXR as a powerful TF, where GLP-1 secretion block is just one of many downstream effects.
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| 5. |
- Oddsson, Asmundur, et al.
(författare)
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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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| 6. |
- Solé Navais, Pol, et al.
(författare)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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Tidskriftsartikel (refereegranskat)abstract
- The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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| 7. |
- Westergren, Albert, et al.
(författare)
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Convergent and discriminant validity of the Minimal Eating Observation Form - version II : a cross-sectional study
- 2024
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Ingår i: BMC Geriatrics. - : BioMed Central Ltd.. - 1471-2318. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND : The Minimal Eating Observation Form - Version II (MEOF-II) is a brief and easy to use screening tool for eating difficulties, that is psychometrically robust. The aim of this study was to explore convergent (measuring similar constructs) and discriminant (measuring somewhat different constructs) validity of the MEOF-II to other validated dysphagia specific, activity and participation related instruments. METHODS : In this cross-sectional study, participants (n = 100, mean age 72, n = 42 women), diagnosed with either chronic pulmonary disease, Parkinson´s disease, Multiple Sclerosis, or stroke were recruited from rehabilitation centres. Patient-reported outcomes and clinical-rated assessments, capturing eating ability in general and swallowing in specific, included: The Dysphagia Handicap Index (DHI), the 4-question test (4QT), the Minimal Eating Observation Form - II, the Volume - Viscosity Swallow Test (V-VST), Flexible Endoscopic Evaluation of Swallowing (FEES) documented according to the Penetration-Aspiration Scale (PAS). Type of oral intake was documented using the Functional Oral Intake Scale (FOIS). Activities in daily living was assessed with Barthel index (BI). Spearman's correlation coefficient was used to analyze associations. The MEOF-II total score was hypothesised to have moderate correlations (r ≥ 0.3) with the other assessments, besides with PAS and FOIS (weak correlations, r < 0.3). RESULTS : In total 78 participants had any type of eating difficulties (MEOF-II), 69 reported dysphagia (4QT), 62 had dysphagia according to V-VST, 29 showed evidence of penetration/aspiration (PAS), and 31 participants had decreased oral intake ability (FOIS). The MEOF-II total score had moderate correlations with DHI, BI, 4QT, V-VST volume, and weak correlations with V-VST dysphagia and viscosity, PAS, and FOIS. Comparing a prior hypothesised correlation strengths against empirical findings showed that 83% of the hypothesised correlations were correct. CONCLUSIONS : The MEOF-II is a holistic and objective screening tool that can indicate the need for further assessment and corresponds well with the persons' subjective experiences. MEOF-II does not specifically assess the risk for penetration/aspiration.
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