Browsing by Subject "Genetics "
Now showing items 1-20 of 218
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21-hydroksylaasin geenivirheet Suomessa : kolme yleisintä mutaatiota selittää 90% tautitapauksista (University of Helsinki, 1995)
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(University of Helsinki, 1992)
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(University of Helsinki, 2000)
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(2020)An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasized the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.
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(2019)Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, =0.27, p=1.3x10(-11)) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p(interaction)=7.0x10(-4), with diabetes=0.69, without diabetes=0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p(Bonferroni)
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(Helsingin yliopisto, 2020)The brainstem monoaminergic neuronal systems are involved in regulation of mood, reward system, memory processing etc. Any defects or damage in these cells lead to many neurological disorders. The brainstem inhibitory GABAergic and excitatory glutamatergic cells in turn control these neuromodulatory neurons. The glutamatergic neurons are found in the Laterodorsal tegmental nucleus (LDTg), Interpeduncular nucleus (IPN) as well as in the Ventral tegmental are (VTA). The LDTg in particular sends these glutamatergic projections to the VTA to regulate their Dopaminergic (DA) neurons. During embryonic development, the brainstem GABAergic and glutamatergic neurons, that regulate the monoaminergic systems, are produced in the ventral rhombomere 1. Their subtypes are known to express various transcription factors (TFs), such as Nkx6-1, Vsx2 and Skor1 marking the glutamatergic neuron precursors in the ventral rhombomere 1. In this thesis project, I studied the expression of another TF, Skor2 in the embryonic brainstem precursors. The basis of the experiment came from an embryonic brainstem single cell mRNA sequencing study performed earlier, where Skor2 expression was observed in the cluster of neurons containing Nkx6-1, Vsx2 and Skor1 expressing cells. Based on this, I hypothesized that Skor2 expression could be seen in glutamatergic precursors in the ventral rhombomere (rV2) domain as well as later in the LDTg nucleus derived from these precursors. To test this, I performed immunohistochemistry (IMHC) studies on a transgenic mouse line expressing Green Fluorescent Protein (GFP) from the Skor2 locus. In the second part of the thesis, I hypothesized that the Skor2 positive cells need this TF for their differentiation. To study this aspect, I performed similar IMHC studies on homozygous Skor2GFP/GFP mice, where Skor2 had been inactivated. My study showed that Skor2 positive cells expressed markers Nkx6-1 and Vsx2 and represented a specific subgroup of early embryonic post-mitotic precursors in the rV2 domain. Later in the brainstem, in contrast to my initial hypothesis, I did not observe Skor2 expression in the LDTg glutamatergic region. Instead, I observed Skor2 positive cells in a region more lateral to the Ventral and Dorsal tegmental nuclei of Gudden. In the homozygous Skor2 mutants, I observed no changes in cell fate during embryonic development. Based on my results, the TF Skor2 is expresses in the glutamatergic precursors and neurons in the rhombomere 1, but form a part of a new cluster of cells away from the LDTg. These neurons have not been studied in detail. However, the Ventral and Dorsal tegmental nuclei of Gudden have been shown to regulate memory and navigation. It is possible that the Skor2 expressing neurons also participate in these functions. Identification of specific molecular markers, such as Skor2, for these neurons now allows their focused functional studies. Skor2 and Skor1 are related TFs belonging to Ski family of transcriptional repressors and are seen to be expressed together. Further investigations into the roles and functional redundancy of these two TFs can be performed using mice carrying mutations in both of these genes.
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(2016)Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
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(University of Helsinki, 1999)
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(Helsingin yliopisto, 2019)Uterine leiomyoma (also known as myoma) is the most common neoplasia in women during reproductive age and it represents a burden for public health care. Approximately 70% of Caucasian women develop myomas, although only 25% of cases are symptomatic. The genetic background of myomas varies significantly and the most common genetic causes are mutations in genes Mediator complex subunit 12 (MED12), Fumarate hydratase (FH) or YEATS Domain containing 4 (YEATS4) , rearrangements affecting the High Mobility Group AT-hook 2 (HMGA2), and deletions in COL4A5/6 locus. MED12 mutations represent the most common genetic alteration in myomas, being present in approximately 70% of cases. Genome organization comprises different levels of complexity, spanning from regulation of individual genes to changes in the architecture of large portions of chromosomes. Literature offers massive evidence of changes in genome organization among different cell types and between several tumor and related healthy cells, but information about these changes in myoma is lacking. The aim of this study is to determine the main features of genome organization in myomas belonging to the aforementioned five genetic subclasses, in order to identify which are the underlying common pathways that are dysregulated in the neoplasia. This is achieved by mapping regions of open chromatin in myomas and related my-ometrium samples with ATAC-seq. Sample’s clustering seems not to be individual-dependent, while tumors belonging to FH, YEATS4 and COL4A5/6 subclasses form distinct clusters, unlike MED12 and HMGA2 subclasses. Six open chromatin regions located within genes were identified in 19/25 tumors and not in myometrium. Seven myometrium-specific open chromatin regions were identified in 21/25 myometria and in less than 10 tumors. As expected, Gene Ontology enrichment analysis revealed that myomas belonging to FH subclass are characterized by deregulation of metabolic pathways. Many of the identified genes in the open chromatin regions have been linked to other tumors in previous studies. Tumor-specific open chromatin regions locate within oncogenes, while myometrium-specific ones are found in proximity of tumor suppressor genes, suggesting a biological role in myomagenesis for these genes. Further investigation on the identified genes (e.g. transcriptional regulation, gene expression and protein level) and addi-tional studies on chromatin architecture are needed to fully unravel the mechanism of myomagenesis.
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(Helsingin yliopisto, 2020)The human gut is inhabited by gut microbiota, a complex and diverse ecological community of trillions of microbes that affect both the normal human physiology and countless disease states and susceptibilities. Understanding the composition, functions and the causes and effects of changes in the microbiota is invaluable for understanding diseases that are connected to the microbiota and developing better treatments to the diseases. The gut microbiota varies between individuals and keeps changing over time. Behind the variability are e.g. the person’s age, genetics, diet, environment, and especially diseases and the use of antibiotics. When antibiotic use disrupts the gut microbiota, the changes can persist for years. Antibiotic resistance tends to increase after the use of antibiotics. Since antibiotic resistance in bacterial pathogens is considered a major health threat, the characterization of the human gut resistome (the antibiotic resistance genes (ARGs) found in the gut microbiota) is of great medical interest. Next-generation sequencing techniques have enabled studying also those microbe species that cannot be cultured at the moment. Metagenomics provides information on all genetic material collected from a given environment and enables searching for any sequences of interest within it, e.g. ARG sequences. The development of Parkinson’s disease (PD) is suspected to begin in the enteric nervous system and spread from there toward the central nervous system. The use of antibiotics could be linked to PD through their effects on gut microbiota, and since these effects are modified by the gut resistome, the aim of this study was to find gene sequences coding antibiotic resistance in human gut metagenomics data originating from stool samples of PD patients and healthy controls, and to find out potential differences in the occurrence of antibiotic resistance genes in the gut microbes of the two study groups. DeepARG was the chosen method for searching antibiotic resistance gene sequences in the metagenomics data. The statistical data analyses, including alpha diversity, multivariate analyses, and differential abundance analysis, were performed with the R statistical programming language in RStudio. DeepARG found 840 different ARGs in 192 samples. The ARGs belonged to 29 different ARG classes. The alpha diversity analysis showed a small estimated difference between PD and control groups indicating a possible slightly higher ARG diversity in the PD group. Multivariate analysis did not give any strong suggestions of definite biologically meaningful differences between the study groups. 16 ARGs were deemed differentially abundant in the study groups. BepE, cmeA, cmlv, dfrE, mefC, msrB, opcM, oprM and RbpA seemed to have increased abundance, and arnC, BN537_02049, dfrK, mgrA, murA, tet35 and tetT were suggested to have decreased abundance in PD patients compared to the healthy controls. These ARGs do not appear interconnected in any other way except for some sharing antibiotic types to which they offer resistance, and some having similar resistance mechanisms. In the light of an ongoing, unpublished epidemiological study of the connection between PD and the use of antibiotics it would seem that only three ARGs (msrB, mefC and dfrE) might be somehow relevant in PD development, but their effects, if any, are most likely minor. Eight ARG classes were shown to have differential abundance between PD patients and healthy controls. Bacitracin, fosfomycin and polymyxin classes showed decrease and chloramphenicol, fosmidomycin, puromycin, rifampin and sulfonamide classes showed increase in abundance in PD compared to controls. The change in the abundance of a certain ARG could reflect change in the abundance of the bacteria carrying that resistance gene. If so, the follow-up questions would be how much change in the abundance of bacteria is due to the use of certain antibiotics and how much is caused by environmental factors. It also remains to be studied whether specific antibiotics associated with the ARGs that in this study showed differential abundance in PD patients and healthy controls might have an actual role in PD development. The results of this thesis study are later to be combined with and further studied alongside information coming from ongoing studies on antibiotics use in general population and in PD patients. While this study did not concentrate its efforts into finding novel ARGs, the metagenomics dataset could also in the future be applied for that purpose.
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(University of Helsinki, 1999)
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(University of Helsinki, 1996)
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(2019)Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.
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(BioMed Central, 2018)Abstract Background Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Methods Five thousand one hundred pregnant women of gestational age 24–28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. Results In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. Conclusions GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.
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(2018)Background: Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Methods: Five thousand one hundred pregnant women of gestational age 24-28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. Results: In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p <0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. Conclusions: GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.
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(2020)Subclinical psychosis, including schizotypal indicators and psychotic experiences, predicts future suicidal ideation. This relationship may reflect unmeasured confounding from environmental factors, genetic factors, or both. We used a genetically-informative twin design to understand if the association between subclinical psychosis and suicidal ideation is independent of shared genetic and environmental factors. We analysed cross-sectional associations of age-22 self-reported subclinical psychosis (positive, negative, and disorganised features) with suicidal ideation in twins participating in the FinnTwin12 study (maximum n = 1213). Then, we analysed the reverse association of age-14 suicidal ideation with age-22 subclinical psychosis. Associations were studied first among individuals and then within monozygotic (MZ) and dizygotic (DZ) pairs. Individual-level analyses showed that all subclinical psychosis factors were associated with suicidal ideation. In within-pair analyses, estimates of associations were lower for MZ pairs than DZ pairs, except for the negative schizotypy-suicidal ideation association where estimates were consistent across individual-level and within-pair analyses. Findings provide evidence that the association between negative features and suicide ideation is not explained by familial factors and may be causal, though the possibility of confounding by individual-specific environmental factors and reverse causation cannot be ruled out. The relationships of positive and disorganised subclinical psychosis features with suicidal ideation cannot be explained by confounding due to environmental factors shared between siblings, but their associations may be due to shared genetic factors. (C) 2020 Elsevier B.V. All rights reserved.
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(2023)Background:Preexisting hypertension increases risk for preeclampsia. We examined whether a generic blood pressure polygenic risk score (BP-PRS), compared with a preeclampsia-specific polygenic risk score (PE-PRS), could better predict hypertensive disorders of pregnancy.Methods:Our study sample included 141 298 genotyped FinnGen study participants with at least one childbirth and followed from 1969 to 2021. We calculated PRSs for SBP and preeclampsia using summary statistics for greater than 1.1 million single nucleotide polymorphisms.Results:We observed 8488 cases of gestational hypertension (GHT) and 6643 cases of preeclampsia. BP-PRS was associated with GHT [multivariable-adjusted hazard ratio for 1SD increase in PRS (hazard ratio 1.38; 95% CI 1.35-1.41)] and preeclampsia (1.26, 1.23-1.29), respectively. The PE-PRS was also associated with GHT (1.16; 1.14-1.19) and preeclampsia (1.21, 1.18-1.24), but with statistically more modest magnitudes of effect (P = 0.01). The model c-statistic for preeclampsia improved when PE-PRS was added to clinical risk factors (P = 4.6 x 10(-15)). Additional increment in the c-statistic was observed when BP-PRS was added to a model already including both clinical risk factors and PE-PRS (P = 1.1 x 10(-14)).Conclusion:BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation.
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(2023)Age at maturity can vary dramatically within some species. We show that, when raised in controlled conditions, Atlantic salmon age at maturity is affected greatly by temperature as well as a recently discovered age-at-maturity gene. The influence of temperature on age at maturity differed between two populations, but the effect of the age-at-maturity gene was similar in both temperatures and populations.Age at maturity is a key life history trait involving a trade-off between survival risk and reproductive investment, and is an important factor for population structures. In ectotherms, a warming environment may have a dramatic influence on development and life history, but this influence may differ between populations. While an increasing number of studies have examined population-dependent reactions with temperature, few have investigated this in the context of maturation timing. Atlantic salmon, a species of high conservation relevance, is a good study species for this topic as it displays considerable variation in age at maturity, of which a large proportion has been associated with a genomic region including the strong candidate gene vgll3. Until now, the effect of this gene in the context of different environments and populations has not been studied. Using a large-scale common-garden experiment, we find strong effects of temperature, population-of-origin, and vgll3 genotype on maturation in 2-year-old male Atlantic salmon (Salmo salar). With a temperature difference of 1.8 degrees C, maturation probability was 4.8 times higher in the warm treatment than the cold treatment. This temperature effect was population-specific and was higher in the southern (60.48 degrees N) compared to the northern (65.01 degrees N) population. The early maturation vgll3*E allele was associated with a significantly higher maturation probability, but there was no vgll3 interaction with temperature or population. Both body condition and body mass associated with maturation. The body mass association was only present in the warm treatment. Our findings demonstrate that (i) populations can vary in their response to temperature change in terms of age at maturity, (ii) high intrinsic growth could be associated with higher thermal sensitivity for life history variation and (iii) vgll3 effects on age at maturity might be similar between populations and different thermal environments.
