| 1. |
- Beaumont, Robin N, et al.
(author)
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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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In: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
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Journal article (peer-reviewed)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. |
- Frederiksen, Line Elmerdahl, et al.
(author)
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Psychiatric disorders in childhood cancer survivors in Denmark, Finland, and Sweden : a register-based cohort study from the SALiCCS research programme
- 2022
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In: The Lancet Psychiatry. - 2215-0366 .- 2215-0374. ; 69
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Journal article (peer-reviewed)abstract
- Background: A childhood cancer diagnosis and treatment-induced somatic late effects can affect the long-term mental health of survivors. We aimed to explore whether childhood cancer survivors are at higher risk of psychiatric disorders later in life than their siblings and the general population. Methods: In this register-based cohort study (part of the Socioeconomic Consequences in Adult Life after Childhood Cancer [SALiCCS] research programme), we included 5-year survivors of childhood cancer diagnosed before 20 years of age between Jan 1, 1974 and Dec 31, 2011, in Denmark, Finland, and Sweden. In Denmark and Sweden, 94·7% of individuals were born in a Nordic country (ie, Denmark, Finland, Iceland, Norway, or Sweden); similar information was not available in Finland. Data on ethnicity were not collected. Survivors were compared with their siblings and randomly selected individuals from the general population who were matched to the survivors by year of birth, sex, and geographical region. We followed up our study population from 5 years after the childhood cancer diagnosis or corresponding calendar date for matched individuals (the index date) until Aug 11, 2017, and assessed information on hospital contacts for any and specific psychiatric disorders. For siblings, the index date was defined as 5 years from the date on which they were of the same age as their sibling survivor when diagnosed with cancer. Findings: The study population included 18 621 childhood cancer survivors (9934 [53·3%] males and 8687 [46·7%] females), 24 775 siblings (12 594 [50·8%] males and 12 181 [49·2%] females), and 88 630 matched individuals (47 300 [53·4%] males and 41 330 [46·6%] females). The cumulative incidence proportion of having had a psychiatric hospital contact by 30 years of age between Jan 1, 1979, and Aug 11, 2017, was 15·9% (95% CI 15·3–16·5) for childhood cancer survivors, 14·0% (13·5–14·5) for siblings, and 12·7% (12·4–12·9) for matched individuals. Despite a small absolute difference, survivors were at higher relative risk of any psychiatric hospital contact than their siblings (1·39, 1·31–1·48) and matched individuals (hazard ratio 1·34, 95% CI 1·28–1·39). The higher risk persisted at the age of 50 years. Survivors had a higher burden of recurrent psychiatric hospital contacts and had more hospital contacts for different psychiatric disorders than their siblings and the matched individuals. Interpretation: Childhood cancer survivors are at higher long-term risk of psychiatric disorders than their siblings and matched individuals from the general population. To improve mental health and the overall quality of life after childhood cancer, survivorship care should include a focus on early signs of mental health problems, especially among high-risk groups of survivors. Funding: NordForsk, Aarhus University, Swedish Childhood Cancer Foundation, Danish Health Foundation, and Swiss National Science Foundation.
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| 3. |
- Jin, S. C., et al.
(author)
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Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
- 2020
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:10
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Journal article (peer-reviewed)abstract
- Whole-exome sequencing of 250 parent-offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder. In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1AandCTNNB1) met genome-wide significance. We identified two novel monogenic etiologies,FBXO31andRHOB, and showed that theRHOBmutation enhances active-state Rho effector binding while theFBXO31mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in aDrosophilareverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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| 4. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 5. |
- Nielsen, Christoffer T, et al.
(author)
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Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation.
- 2012
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In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:4, s. 1227-1236
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Journal article (peer-reviewed)abstract
- OBJECTIVE.: To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in systemic lupus erythematosus (SLE) and to correlate this with clinical and serological parameters. METHODS.: Sixty-eight clinically well-characterized SLE patients, 38 healthy controls (HC), 6 systemic sclerosis (SSc), and 6 rheumatoid arthritis (RA) patients were included. The numbers of annexin V-binding MPs displaying IgG, IgM or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP-IgG load was determined by flow cytometry of all SLE and HC samples. RESULTS.: SLE patients had significantly increased total and relative numbers of IgG-positive MPs (p = 0.0004) with a much higher average IgG-load/MP (p < 0.0001) than HCs. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q in SLE. In RA and SSc the average IgG/MP was significantly lower than in SLE (p = 0.006 and 0.05, respectively). Also, IgM/MP and C1q/MP were higher in SLE than in controls (p < 0.05) except for IgM in the RA-group. IgG-positive MPs were significantly associated with the presence of anti-dsDNA, anti-ENA, and anti-histone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG/MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and with complement consumption. CONCLUSIONS.: Circulating cell-derived MPs in SLE carry increased loads of IgG, IgM, and C1q and IgG-MPs are associated with autoantibodies and complement activation. The findings link immunological reactions on MPs with the etiopathology of SLE. © 2012 American College of Rheumatology.
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| 6. |
- Solé Navais, Pol, et al.
(author)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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In: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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Journal article (peer-reviewed)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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| 9. |
- Aberg, Fredrik, et al.
(author)
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Differences in long-term mortality among liver transplant recipients and the general population: A population-based Nordic study.
- 2015
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In: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 61:2, s. 668-677
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Journal article (peer-reviewed)abstract
- Dramatic improvement in first-year outcomes post-liver transplantation (LT) has shifted attention to long-term survival, where efforts are now needed to achieve improvement. Understanding the causes for premature death is a prerequisite for improving long-term outcome. Overall and cause-specific mortality of 3299 Nordic LT patients (1985-2009) having survived 1 year post-LT were divided by expected rates in the general population, adjusted for age, sex, calendar time, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver-Transplant Registry and WHO mortality-indicator database. Stagnant patient survival rates >1 year post-LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95%CI 5.4-6.3), with improvement from 1985-1999 to 2000-2010 in hepatitis C (HCV) (SMR change 23.1-9.2), hepatocellular carcinoma (HCC) (SMR 38.4-18.8), and primary sclerosing cholangitis (SMR 11.0-4.2), and deterioration in alcoholic liver disease (8.3-24.0) and acute liver failure (ALF) (5.9-7.6). SMRs for cancer and liver disease (recurrent or transplant-unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22-693) and kidney disease (SMR 13-45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant-specific events caused 16% of deaths. Conclusion: standardized premature mortality provided an improved picture of long-term post-LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow-up and future research. (Hepatology 2014;).
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