Genomic imprinting in complex traits

https://www.ester.ee/record=b5052734*es

Geneetilise vermimise mõju komplekstunnustele

Väitekirja elektrooniline versioon ei sisalda publikatsiooneJuba 1980. aastate alguses läbi viidud katsed loomade rakutuumade siirdamisega tõid esile epigeneetilise nähtuse, mida hakati nimetama geneetiliseks vermimiseks (genomic imprinting). Selle fenomeni tõttu tekivad vanemaspetsiifilised erinevused geenide ekspressioonis. Diploidses organismis ekspresseeruvad tavaliselt mõlemalt vanemalt päritud geenikoopiad. Vermitud geenide puhul ekspresseerub ainult üks geenikoopia, samas kui teine koopia on inaktiveeritud. Nüüdseks on inimestel leitud juba peaaegu 150 vermitud geeni. Kuna geneetilise vermimise eeldused tekivad sugurakkudes, arvati pikka aega, et see muster püsib sarnasena kõikides kudedes. Uuemad tööd, milles on kasutatud inimeste ja katseloomade erinevaid rakke on siiski näidanud, et vermitud geenide ekspressioonimuster sõltub nii koest kui ka organismi arengujärgust. Enamik vermitud geene on leitud platsentast või embrüonaalsetest kudedest ning on vähe informatsiooni samade geenide ekspressioonimustrite kohta täiskasvanud organismi kudedes. Seetõttu on oluline uurida iga vermitud geeni vermimismudelit erinevates kudedes, et oleks võimalik hinnata selle geeni mõju haigusele. Käesoleva töö raames uurisime vermitud geenide ning nendega seotud kontrollregioonide metülatsioonimustreid, kasutades selleks täiskasvanud inimese somaatilisi kudesid. Koeproovide uurimisel leidsime, et vermitud geene iseloomustab promootori-spetsiifilises piirkonnas suurema arvu poolmetüleeritud nukleotiidide esinemine, mis võib viidata vanema-spetsiifilisele metülatsioonile. Lisaks tuvastasime, et ICR-id geeniregioonides, mis olid algselt vermitud sugurakkudes ehk ootsüütides ja spermatosoidides, võivad hiljem somaatilistes rakkudes oma poolmetüleeritud oleku kaotada. Hilisemad uuringud on seostanud poolmetüleeritud oleku kadu geenide bialleelse ekspressiooniga. Seetõttu on alust oletada, et, platsentas vermitud geenid võivad hilisemates arengustaadiumites omada bialleelset ekspressiooni.In the early 1980 the animal nucleus transplantation experiments revealed an epigenetic phenomenon, later called as genomic imprinting, resulting in genes expressed in a parent-of-origin manner. In diploid organism, the somatic cells express both parental copies of a gene, whereas imprinted genes demonstrate expression only from one allele, while the second one remains deactivated. As for 2018, nearly 150 imprinted genes have been identified in humans. Being established in the germline, genomic imprints were thought to have identical patterns within an organism. Later, studies in animals and humans have demonstrated that the expression of imprinted genes may depend on the specific tissue and the developmental stage of an organism. To date most of the genes has been detected as imprinted in placenta or embryonic tissues, and there is a limited information about imprinted expression in an adult organism. Thus comprehensive imprinted expression analysis would shed light onto the specific tissues and developmental stage of an organism. In this thesis we aimed to define the methylation patterns for imprinted genes and germline differentially methylated regions in somatic tissues of adult organisms. We identified an imprinting-specific methylation pattern that is characterized by an increased number of intermediately methylated probes within a specific area of the promoter. We also detected the loss of methylation for placenta-specific germline DMRs. Thus, it is highly probable that genes that were detected as imprinted in placenta have biallelic expression in tissues somatic tissues of an organism

A distinctive DNA methylation pattern in insufficient sleep

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 +/- 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 +/- 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value <0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.Peer reviewe

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

Publisher Copyright: © 2022, The Author(s).We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.Peer reviewe

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 x 10(-8)) with GDM, mapping to/near MTNR1B (P = 4.3 x 10(-54)), TCF7L2 (P = 4.0 x 10(-16)), CDKAL1 (P = 1.6 x 10(-4)), CDKN2A-CDKN2B (P = 4.1 x 10(-9)) and HKDC1 (P = 2.9 x 10(-8)). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.Peer reviewe

Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) 350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.Peer reviewe

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the fi