Browsing by Author "Metspalu, Andres"

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Characterization of the 16p11.2 600 kb BP4-BP5 CNVs in adult population cohort
(Tartu Ülikool, 2016) Kolk, Berit; Männik, Katrin; Metspalu, Andres; Tartu Ülikool. Loodus- ja tehnoloogiateaduskond; Tartu Ülikool. Molekulaar- ja rakubioloogia instituut
The 16p11.2 BP4-BP5 600 kb deletion and duplication carriers from clinical cohorts result in syndromes that affect neurodevelopment and anthropometric traits, but are also characterized by variable expressivity of associated phenotypic outcomes. The phenotype analysis showed that the 16p11.2 CNV carriers in the EGC UT adult population have characteristic features of 16p11.2 600 kb syndromes. Additionally, the adult cohort has common features, which are significantly recurrent comparing to EGC UT general population. Also, a new approach was used for finding genetic modifiers contributing to the variability of genomic disorders phenotypes. The wholeexome analysis found potential modifying substitutions for 4 adult 16p11.2 CNV carriers’ specific features. According to our phenotypic and genotypic findings, it is important to conduct a detailed phenotypic assessment of individuals with particular genetic disorder and further investigate the exome or genome of the carriers to more precisely predict the severity and diverse outcomes of disease.
Demographic associations for autoantibodies in disease-free individuals of a European population
(2016) Haller-Kikkatalo, Kadri; Alnek, Kristi; Metspalu, Andres; Mihailov, Evelin; Metsküla, Kaja; Kisand, Kalle; Pisarev, Heti; Salumets, Andres; Uibo, Raivo
The presence of autoantibodies usually precedes autoimmune disease, but is sometimes considered an incidental finding with no clinical relevance. The prevalence of immune-mediated diseases was studied in a group of individuals from the Estonian Genome Project (n = 51,862), and 6 clinically significant autoantibodies were detected in a subgroup of 994 (auto)immune-mediated disease-free individuals. The overall prevalence of individuals with immune-mediated diseases in the primary cohort was 30.1%. Similarly, 23.6% of the participants in the disease-free subgroup were seropositive for at least one autoantibody. Several phenotypic parameters were associated with autoantibodies. The results suggest that (i) immune-mediated diseases are diagnosed in nearly one-third of a random European population, (ii) 6 common autoantibodies are detectable in almost one-third of individuals without diagnosed autoimmune diseases, (iii) tissue non-specific autoantibodies, especially at high levels, may reflect preclinical disease in symptom-free individuals, and (iv) the incidental positivity of anti-TPO in men with positive familial anamnesis of maternal autoimmune disease deserves further medical attention. These results encourage physicians to evaluate autoantibodies in addition to treating a variety of patient health complaints to detect autoimmune-mediated disease early.
Identifying common and rare variants in migraine genetic predisposition
(Tartu Ülikool, 2016) Lorenz, Anna-Liisa; Metspalu, Andres; Kolk, Anneli; Tartu Ülikool. Loodus- ja tehnoloogiateaduskond; Tartu Ülikool. Molekulaar- ja rakubioloogia instituut
Migraine is an episodic brain disorder that is characterized by recurrent pain. Etiology of migraine is extremely complex; most likely caused by combination of genetic and environmental risk factors. The aim of the thesis is to examine the role of MTHFR polymorphisms rs1801131 and rs1801133 as risk factors for pediatric migraine; also in migraine subtypes – migraine with aura (MA) and without aura (MO). Second part involved exome sequencing of two family trios to discover novel genetic risk factors for migraine. Candidate gene study of MTHFR did not reveal any statistically significant results. Exome sequencing revealed three novel variants that could precipitate migraine. PDLIM5, PRKCE and SCN9A all affect voltage-gated channels. Mutations in those genes could increase neuronal hyperexcitability and neurotransmitter release, which in turn has been associated with pain and visual aura.
Imprinted genes and imprinting control regions show predominant intermediate methylation in adult somatic tissues
(Epigenomics, 2016-03) Pervjakova, Natalia; Kasela, Silva; Morris, Andrew P; Kals, Mart; Metspalu, Andres; Lindgren, Cecilia M; Salumets, Andres; Mägi, Reedik
Genomic imprinting is an epigenetic feature characterized by parent-specific monoallelic gene expression. The aim of this study was to compare the DNA methylation status of imprinted genes and imprinting control regions (ICRs), harboring differentially methylated regions (DMRs) in a comprehensive panel of 18 somatic tissues. The germline DMRs analyzed were divided into ubiquitously imprinted and placenta-specific DMRs, which show identical and different methylation imprints in adult somatic and placental tissues, respectively. We showed that imprinted genes and ICR DMRs maintain methylation patterns characterized by intermediate methylation levels in somatic tissues, which are pronounced in a specific region of the promoter area, located 200–1500 bp from the transcription start site. This intermediate methylation is concordant with gene expression from a single unmethylated allele and silencing of a reciprocal parental allele through DNA methylation. The only exceptions were seen for ICR DMRs of placenta-specific imprinted genes, which showed low levels of methylation, suggesting that these genes escape parent-specific epigenetic regulation in somatic tissues.
Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions
(2017) Shungin, Dmitry; Deng, Wei Q.; Varga, Tibor V.; Luan, Jian'an; Mihailov, Evelin; Metspalu, Andres; GIANT Consortium; Morris, Andrew P.; Forouhi, Nita G.; Lindgren, Cecilia; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Hallmans, Göran; Chu, Audrey Y.; Justice, Anne E.; Graff, Mariaelisa; Winkler, Thomas W.; Rose, Lynda M.; Langenberg, Claudia; Cupples, L. Adrienne; Kilpeläinen, Tuomas O.; Scott, Robert A.; Mägi, Reedik; Paré, Guillaume; Franks, Paul W.; Ridker, Paul M.; Wareham, Nicholas J.; Ong, Ken K.; Loos, Ruth J. F.; Chasman, Daniel I.; Ingelsson, Erik
Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman’s ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman’s ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial <0.05). SNPs from the top 1% of the Pm distribution for BMI had more significant Pv values (PMann–Whitney = 1.46×10−5), and the odds ratio of SNPs with nominally significant (<0.05) Pm and Pv was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 8.63×10−9 and 8.52×10−7 for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them.
The genetic architecture of sporadic and multiple consecutive miscarriage
(Nature Communications, 2020-11-25) Laisk, Triin; Soares, Ana Luiza G.; Lindgren, Cecilia M.; Ferreira, Teresa; Painter, Jodie N.; Censin, Jenny C.; Laber, Samantha; Bacelis, Jonas; Chen, Chia-Yen; Lepamets, Maarja; Lawlor, Deborah A.; Mägi, Reedik; Medland, Sarah E.; Granne, Ingrid; Walters, Robin G.; Nielsen, Rasmus; Neale, Benjamin M.; Martin, Nicholas G.; Li, Liming; Jacobsson, Bo; Conrad, Donald F.; Chen, Zhengming; Werge, Thomas; Zondervan, Krina; Snieder, Harold; Salumets, Andres; Seminara, Stephanie; Lippincott, Margaret; Nyholt, Dale R.; Nordentoft, Merete; Njølstad, Pål R.; Mortensen, Preben B.; Mors, Ole; Morris, Andrew P.; Montgomery, Grant W.; Metspalu, Andres; Lind, Penelope A.; Kukushkina, Viktorija; Kartsonaki, Christiana; Juodakis, Julius; Johansson, Stefan; Jin, Xin; Hougaard, David M.; Helgeland, Øyvind; Bybjerg-Grauholm, Jonas; Gordon, Scott D.; Børglum, Anders D.; Becker, Christian M.; Yang, Ling; Andersen, Marianne S.; Southcombe, Jennifer; Ramu, Avinash; Millwood, Iona Y.; Liu, Siyang; Lin, Kuang
Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.