ORCID Profile
0000-0002-5323-3102
Current Organisations
University of Tartu
,
University of Glasgow
,
University of Glasgow College of Social Sciences
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Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 21-11-2016
DOI: 10.1038/NG.3725
Publisher: Wiley
Date: 02-12-2019
DOI: 10.1002/AJMG.B.32700
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: BMJ
Date: 29-08-2013
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
Publisher: Routledge
Date: 15-03-2007
Publisher: Research Square Platform LLC
Date: 10-08-2021
DOI: 10.21203/RS.3.RS-688986/V1
Abstract: We performed a trans-ethnic Epigenome Wide Association study on 22,774 in iduals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We found 1,511 independent differentially methylated loci associated with CRP. These CpG sites showed correlation structures across chromosomes, and were primarily situated in euchromatin, depleted in CpG islands and enriched in transcription factor binding sites and genomic enhancer regions. Mendelian randomisation analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis revealed obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we found that a fully activated CpG signature, meaning that if all novel discovered CpGs would either be fully methylated or unmethylated depending on their CRP associated direction of effect, the risk of myocardial infarction would be increased by 20.3%, risk of T2D by 11.3% and the risk of COPD by 5.6%.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2014
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
DOI: 10.1038/S41467-021-27198-4
Abstract: Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant ( p 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9 , the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH , 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2022
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41591-020-0893-5
Abstract: Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable 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. While 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 analyze pLoF variants in LRRK2 observed across 141,456 in iduals sequenced in the Genome Aggregation Database (gnomAD) 9 , 49,960 exome-sequenced in iduals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 in iduals with high-confidence pLoF variants in LRRK2 . Experimental validation of three variants, combined with previous work 10 , confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2019
DOI: 10.1038/S41467-019-12283-6
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients ( F ROH ) for .4 million in iduals, we show that F ROH is significantly associated ( p 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.
Publisher: Public Library of Science (PLoS)
Date: 18-03-2015
Publisher: Springer Science and Business Media LLC
Date: 17-06-2021
Publisher: Springer Science and Business Media LLC
Date: 22-10-2015
DOI: 10.1038/NCOMMS9570
Abstract: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 in iduals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age’ of an in idual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Elsevier BV
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/NG.3211
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
DOI: 10.1038/NG.3412
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/NG.3698
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2016
Abstract: In iduals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including ,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2021
DOI: 10.1186/S13059-021-02398-9
Abstract: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Leveraging DNA methylation and SNP data from more than 40,000 in iduals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1038/S41586-021-03767-X
Abstract: The genetic make-up of an in idual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Publisher: Springer Science and Business Media LLC
Date: 10-07-2017
DOI: 10.1038/NG.3912
Abstract: Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated in iduals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 × 10
Publisher: Springer Science and Business Media LLC
Date: 26-04-2018
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: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NATURE13545
Publisher: Wiley
Date: 23-02-2019
DOI: 10.1002/AJMG.B.32716
Publisher: Elsevier BV
Date: 05-2015
Publisher: Springer Science and Business Media LLC
Date: 25-03-2019
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41588-018-0297-3
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Publisher: Oxford University Press (OUP)
Date: 09-01-2013
DOI: 10.1093/HMG/DDS551
Publisher: Springer Science and Business Media LLC
Date: 21-03-2017
DOI: 10.1038/NCOMMS14774
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique in iduals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6 P =1 × 10 −4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS ( P =8.4 × 10 −7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2023
Publisher: Springer Science and Business Media LLC
Date: 02-03-2023
Publisher: Public Library of Science (PLoS)
Date: 08-05-2015
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
Publisher: Springer Science and Business Media LLC
Date: 24-04-2017
DOI: 10.1038/NG.3841
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
Publisher: Wiley
Date: 11-12-2015
DOI: 10.1002/AJMG.B.32402
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: Elsevier BV
Date: 03-2015
Publisher: Springer Science and Business Media LLC
Date: 30-09-2022
DOI: 10.1038/S41586-022-05165-3
Abstract: Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control in iduals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control in iduals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: eLife Sciences Publications, Ltd
Date: 15-01-2019
DOI: 10.7554/ELIFE.39856
Abstract: We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. In idual genetic variants that increase dementia, cardiovascular disease, and lung cancer – but not other cancers – explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed ( xref ref-type="decision-letter" rid="SA1" see decision letter /xref ).
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: Springer Science and Business Media LLC
Date: 09-12-2021
DOI: 10.1038/S41467-021-27234-3
Abstract: Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1 , PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1 , LDB2 , CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
Publisher: Springer Science and Business Media LLC
Date: 27-01-2016
DOI: 10.1038/NATURE16549
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
Publisher: Springer Science and Business Media LLC
Date: 03-05-2022
DOI: 10.1038/S41467-022-29792-6
Abstract: We performed a multi-ethnic Epigenome Wide Association study on 22,774 in iduals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2016
DOI: 10.1038/NCOMMS13357
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain % of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5 / C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2015
DOI: 10.1038/NG.3390
Publisher: Springer Science and Business Media LLC
Date: 11-07-2016
DOI: 10.1038/NATURE18642
Publisher: Springer Science and Business Media LLC
Date: 22-01-2021
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: American Medical Association (AMA)
Date: 04-2019
DOI: 10.1001/JAMAPSYCHIATRY.2018.4175
Abstract: Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear physical activity may protect against depression, and/or depression may result in decreased physical activity. To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference. This 2-s le mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes—self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)—and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in erse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR–Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018. MDD and physical activity. GWAS summary data were available for a combined s le size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration 95% CI, 0.59-0.92 P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = −0.08 in mean acceleration per MDD vs control status 95% CI, −0.47 to 0.32 P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity 95% CI, 0.57-3.37 P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status 95% CI, −0.008 to 0.05 P = .15). Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed—but not self-reported—physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.
Publisher: Public Library of Science (PLoS)
Date: 10-2015
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: 13-10-2017
DOI: 10.1038/S41467-017-00934-5
Abstract: Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents’ survival, we discover two regions associated with longevity ( HLA-DQA1/DRB1 and LPA ). We also validate previous suggestions that APOE , CHRNA3/5 , CDKN2A/B , SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2021
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Springer Science and Business Media LLC
Date: 11-06-2019
DOI: 10.1038/S41467-019-10461-0
Abstract: Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Springer Science and Business Media LLC
Date: 28-09-2020
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: Springer Science and Business Media LLC
Date: 08-10-2018
DOI: 10.1038/S42003-018-0155-Y
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected in iduals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Oxford University Press (OUP)
Date: 22-10-2015
DOI: 10.1093/HMG/DDV443
Abstract: Sex-specific genetic effects have been proposed to be an important source of variation for human complex traits. Here we use two distinct genome-wide methods to estimate the autosomal genetic correlation (rg) between men and women for human height and body mass index (BMI), using in idual-level (n = ∼44 000) and summary-level (n = ∼133 000) data from genome-wide association studies. Results are consistent and show that the between-sex genetic correlation is not significantly different from unity for both traits. In contrast, we find evidence of genetic heterogeneity between sexes for waist-hip ratio (rg = ∼0.7) and between populations for BMI (rg = ∼0.9 between Europe and the USA) but not for height. The lack of evidence for substantial genetic heterogeneity for body size is consistent with empirical findings across traits and species.
Publisher: American Medical Association (AMA)
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 12-07-2017
DOI: 10.1038/NCOMMS16015
Abstract: Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined s le of 195,180 in iduals and identify 16 loci associated with grip strength ( P × 10 −8 ) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres ( ACTG1 ), neuronal maintenance and signal transduction ( PEX14, TGFA, SYT1 ), or monogenic syndromes with involvement of psychomotor impairment ( PEX14, LRPPRC and KANSL1 ). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2017
Publisher: Springer Science and Business Media LLC
Date: 08-2017
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
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
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
Abstract: To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European in iduals and exome sequencing of 12,940 in iduals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1–5%) non-coding variants in the whole-genome sequenced in iduals and 99.7% of low-frequency coding variants in the whole-exome sequenced in iduals. Each variant was tested for association with T2D in the sequenced in iduals, and, to increase power, most were tested in larger numbers of in iduals ( % of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Lili Milani.