ORCID Profile
0000-0003-1982-6569
Current Organisations
University of Tartu
,
Boston Children's Hospital
,
Harvard Medical School
,
Broad Institute
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Publisher: Proceedings of the National Academy of Sciences
Date: 08-09-2014
Abstract: We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits).
Publisher: Springer Science and Business Media LLC
Date: 14-03-2016
DOI: 10.1038/NG.3528
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-05-2015
Abstract: Human genomes show extensive genetic variation across in iduals, but we have only just started documenting the effects of this variation on the regulation of gene expression. Furthermore, only a few tissues have been examined per genetic variant. In order to examine how genetic expression varies among tissues within in iduals, the Genotype-Tissue Expression (GTEx) Consortium collected 1641 postmortem s les covering 54 body sites from 175 in iduals. They identified quantitative genetic traits that affect gene expression and determined which of these exhibit tissue-specific expression patterns. Melé et al. measured how transcription varies among tissues, and Rivas et al. looked at how truncated protein variants affect expression across tissues. Science , this issue p. 648 , p. 660 , p. 666 see also p. 640
Publisher: BMJ
Date: 29-08-2013
Publisher: Springer Science and Business Media LLC
Date: 07-09-2017
DOI: 10.1038/S41467-017-00473-Z
Abstract: Transcript co-expression is regulated by a combination of shared genetic and environmental factors. Here, we estimate the proportion of co-expression that is due to shared genetic variance. To do so, we estimated the genetic correlations between each pairwise combination of 2469 transcripts that are highly heritable and expressed in whole blood in 1748 unrelated in iduals of European ancestry. We identify 556 pairs with a significant genetic correlation of which 77% are located on different chromosomes, and report 934 expression quantitative trait loci, identified in an independent cohort, with significant effects on both transcripts in a genetically correlated pair. We show significant enrichment for transcription factor control and physical proximity through chromatin interactions as possible mechanisms of shared genetic control. Finally, we construct networks of interconnected transcripts and identify their underlying biological functions. Using genetic correlations to investigate transcriptional co-regulation provides valuable insight into the nature of the underlying genetic architecture of gene regulation.
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Publisher: Springer Science and Business Media LLC
Date: 24-04-2014
Publisher: Public Library of Science (PLoS)
Date: 12-03-2013
Publisher: Springer Science and Business Media LLC
Date: 12-06-2015
DOI: 10.1038/NCOMMS8208
Publisher: Public Library of Science (PLoS)
Date: 18-03-2015
Publisher: Springer Science and Business Media LLC
Date: 17-06-2021
Publisher: Public Library of Science (PLoS)
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 05-05-2015
DOI: 10.1038/NCOMMS8001
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Oxford University Press (OUP)
Date: 04-2015
DOI: 10.1093/IJE/DYV094
Publisher: Oxford University Press (OUP)
Date: 27-07-2012
DOI: 10.1093/HMG/DDS304
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/NG.3211
Publisher: Proceedings of the National Academy of Sciences
Date: 06-04-2011
Abstract: Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based s les of European ancestry, comprising 26,316 in iduals, with replication genotyping in an additional 21,185 in iduals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex s les ( P = 0.026) and significant ( P 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
Publisher: Springer Science and Business Media LLC
Date: 10-2014
DOI: 10.1038/NATURE13692
Publisher: SAGE Publications
Date: 06-10-2014
Abstract: A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R 2 ≈ 0.02%), reached genome-wide significance ( p 5 × 10 −8 ) in a large discovery s le and were replicated in an independent s le ( p .05). The study also reported associations between educational attainment and indices of SNPs called “polygenic scores.” In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large ( N = 34,428) independent s le. We also found that the scores remained predictive ( R 2 ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of in idual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2012
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2020
DOI: 10.1101/2020.08.13.249813
Abstract: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815 p =3.2×10 −8 ), that interacts with sodium otassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence ( p ×10 −6 ) for cross-disorder GxS interaction (rs7302529, p =1.6×10 −7 rs73033497, p =8.8×10 −7 rs7914279, p =6.4×10 −7 ) implicating various functions. Gene-based analyses identified GxS interaction across disorders ( p =8.97×10 −7 ) with transcriptional inhibitor SLTM . Most significant in SCZ was a MOCOS gene locus (rs11665282 p =1.5×10 −7 ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509 p =1.1×10 −7 ) in a locus containing IDO2 , a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD ( p FDR .05). In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2013
Abstract: Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type–restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type–specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type–restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NATURE13545
Publisher: Elsevier BV
Date: 08-2015
Publisher: American Diabetes Association
Date: 23-02-2015
DOI: 10.2337/DB14-0988
Abstract: Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese in iduals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 in iduals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P & 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the & -year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the & -year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
Publisher: Cold Spring Harbor Laboratory
Date: 24-11-2015
DOI: 10.1101/032789
Abstract: We conducted a genome-wide association study of subjective well-being (SWB) in 298,420 in iduals. We also performed auxiliary analyses of depressive symptoms ("DS" N = 161,460) and neuroticism ( N = 170,910), both of which have a substantial genetic correlation with SWB ( ρ ≈-0.8). We identify three SNPs associated with SWB at genome-wide significance. Two of them are significantly associated with DS in an independent s le. In our auxiliary analyses, we identify 13 additional genome-wide-significant associations: two with DS and eleven with neuroticism, including two inversion polymorphisms. Across our phenotypes, loci regulating expression in central nervous system and adrenal ancreas tissues are enriched. The discovery of genetic loci associated with the three phenotypes we study has proven elusive our findings illustrate the payoffs from studying them jointly.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Oxford University Press (OUP)
Date: 09-01-2013
DOI: 10.1093/HMG/DDS551
Publisher: Public Library of Science (PLoS)
Date: 08-05-2015
Publisher: Springer Science and Business Media LLC
Date: 08-06-2014
DOI: 10.1038/NG.3004
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2795
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2797
Publisher: Springer Science and Business Media LLC
Date: 31-10-2017
DOI: 10.1038/MP.2017.210
Publisher: Springer Science and Business Media LLC
Date: 08-09-2013
DOI: 10.1038/NG.2756
Publisher: Wiley
Date: 31-05-2013
DOI: 10.1002/AJMG.B.32168
Publisher: Elsevier BV
Date: 03-2015
Publisher: Oxford University Press (OUP)
Date: 04-2015
DOI: 10.1093/IJE/DYV082
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
Publisher: Springer Science and Business Media LLC
Date: 25-04-2010
DOI: 10.1038/NG.573
Publisher: Springer Science and Business Media LLC
Date: 05-12-2012
Publisher: Cold Spring Harbor Laboratory
Date: 27-02-2019
DOI: 10.1101/561472
Abstract: Human genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes 1,2 . Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease 3,4 , suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns 5–8 , the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 in iduals sequenced in the Genome Aggregation Database (gnomAD) 9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 in iduals with high-confidence predicted LoF variants in LRRK2 , several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Oxford University Press (OUP)
Date: 23-04-2014
DOI: 10.1093/HMG/DDU183
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
Publisher: Springer Science and Business Media LLC
Date: 31-08-2011
DOI: 10.1038/NATURE10406
Publisher: Springer Science and Business Media LLC
Date: 31-08-2015
DOI: 10.1038/NG.3390
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2020
DOI: 10.1101/2020.02.02.20020065
Abstract: Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2021
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: Wiley
Date: 27-12-2011
DOI: 10.1002/AJMG.B.32013
Publisher: Springer Science and Business Media LLC
Date: 07-2014
DOI: 10.1038/NATURE13595
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NG.3598
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Elsevier BV
Date: 02-2015
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.JACI.2014.12.1870
Abstract: Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. We sought to identify disease associations and the functional effect of BDNF genetic variants in patients with moderate-to-severe AR. Tagging single nucleotide polymorphisms (SNPs) spanning the BDNF gene were selected from the human HapMap Han Chinese from Beijing (CHB) data set, and associations with moderate-to-severe AR were assessed in 2 independent cohorts of Chinese patients (2216 from Shandong province and 1239 living in Singapore). The functional effects of the BDNF genetic variants were determined by using both in vitro and ex vivo assays. The tagging SNP rs10767664 was significantly associated with the risk of moderate-to-severe AR in both Singapore Chinese (P = .0017 odds ratio, 1.324) and Shandong Chinese populations (P = .039 odds ratio, 1.180). The coding nonsynonymous SNP rs6265 was in perfect linkage with rs10767664 and conferred increased BDNF protein secretion by a human cell line in vitro. Subjects bearing the AA genotype of rs10767664 exhibited increased risk of moderate-to-severe AR and displayed increased BDNF protein and total IgE levels in plasma. Using a large-scale expression quantitative trait locus study, we demonstrated that BDNF SNPs are significantly associated with altered BDNF concentrations in peripheral blood. A common genetic variant of the BDNF gene is associated with increased risk of moderate-to-severe AR, and the AA genotype is associated with increased BDNF mRNA levels in peripheral blood. Together, these data indicate that functional BDNF gene variants increase the risk of moderate-to-severe AR.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
DOI: 10.1038/NATURE13005
Publisher: Elsevier BV
Date: 06-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2013
Abstract: Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 s les, Rietveld et al. (p. 1467 , published online 30 May see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Oxford University Press (OUP)
Date: 04-04-2013
DOI: 10.1093/AJE/KWS473
Publisher: Public Library of Science (PLoS)
Date: 20-10-2011
Publisher: Oxford University Press (OUP)
Date: 27-02-2013
DOI: 10.1093/HMG/DDT104
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
Publisher: Springer Science and Business Media LLC
Date: 11-05-2015
DOI: 10.1038/NG.3300
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-05-2015
Abstract: Human genomes show extensive genetic variation across in iduals, but we have only just started documenting the effects of this variation on the regulation of gene expression. Furthermore, only a few tissues have been examined per genetic variant. In order to examine how genetic expression varies among tissues within in iduals, the Genotype-Tissue Expression (GTEx) Consortium collected 1641 postmortem s les covering 54 body sites from 175 in iduals. They identified quantitative genetic traits that affect gene expression and determined which of these exhibit tissue-specific expression patterns. Melé et al. measured how transcription varies among tissues, and Rivas et al. looked at how truncated protein variants affect expression across tissues. Science , this issue p. 648 , p. 660 , p. 666 see also p. 640
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.714
Publisher: Springer Science and Business Media LLC
Date: 14-04-2013
DOI: 10.1038/NG.2610
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
No related grants have been discovered for Tonu Esko.