Publications by authors named "Thibaud S Boutin"

20 Publications

  • Page 1 of 1

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
October 2020

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability.

Clin Epigenetics 2020 07 27;12(1):113. Epub 2020 Jul 27.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Background: Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)-a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure.

Methods: We utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults (n = 889) and a large, cross-sectional cohort (n = 7028).

Results: We identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = - 0.08 and - 0.05); however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = - 0.15 and - 0.08).

Conclusions: An epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of individuals, and thus clearer inference of associations with incident health outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00903-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385981PMC
July 2020

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

PLoS Genet 2020 07 6;16(7):e1008785. Epub 2020 Jul 6.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, United Kingdom.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337286PMC
July 2020

Insights into the genetic basis of retinal detachment.

Hum Mol Genet 2020 03;29(4):689-702

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.

Retinal detachment (RD) is a serious and common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. In the UK Biobank data set, where RD was ascertained by self-report or hospital records, genetic correlations between RD and high myopia or cataract operation were, respectively, 0.46 (SE = 0.08) and 0.44 (SE = 0.07). These correlations are consistent with known epidemiological associations. Through meta-analysis of genome-wide association studies using UK Biobank RD cases (N = 3 977) and two cohorts, each comprising ~1 000 clinically ascertained rhegmatogenous RD patients, we uncovered 11 genome-wide significant association signals. These are near or within ZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1 and LOXL1. Replication in the 23andMe data set, where RD is self-reported by participants, firmly establishes six RD risk loci: FAT3, COL22A1, TYR, BMP3, ZC3H11B and PLCE1. Based on the genetic associations with eye traits described to date, the first two specifically impact risk of a RD, whereas the last four point to shared aetiologies with macular condition, myopia and glaucoma. Fine-mapping prioritized the lead common missense variant (TYR S192Y) as causal variant at the TYR locus and a small set of credible causal variants at the FAT3 locus. The larger study size presented here, enabled by resources linked to health records or self-report, provides novel insights into RD aetiology and underlying pathological pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddz294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068119PMC
March 2020

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

Commun Biol 2019 27;2:435. Epub 2019 Nov 27.

1Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands.

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in and rs1028727 near at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-019-0634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881308PMC
July 2020

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort.

Sci Rep 2019 07 29;9(1):10964. Epub 2019 Jul 29.

MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-47436-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662790PMC
July 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Publisher Correction: Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.

Nat Commun 2019 May 1;10(1):2069. Epub 2019 May 1.

MRC Human Genetic Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

In the original version of this Article, the legend in the upper panel of Figure 2 incorrectly read 'paternal imprinting' and should have read 'maternal imprinting'. This has been corrected in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494888PMC
May 2019

Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.

Nat Commun 2019 03 27;10(1):1383. Epub 2019 Mar 27.

MRC Human Genetic Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09301-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437195PMC
March 2019

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Nat Genet 2019 01 21;51(1):51-62. Epub 2018 Dec 21.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365102PMC
January 2019

Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.

Transl Psychiatry 2018 01 10;8(1). Epub 2018 Jan 10.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, EH10 5HF, Edinburgh, UK.

Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-017-0034-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802463PMC
January 2018

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Nat Commun 2017 10 13;8(1):910. Epub 2017 Oct 13.

Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester, M13 9PL, UK.

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.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715013PMC
October 2017

Exploration of haplotype research consortium imputation for genome-wide association studies in 20,032 Generation Scotland participants.

Genome Med 2017 03 7;9(1):23. Epub 2017 Mar 7.

MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

Background: The Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based population cohort with DNA, biological samples, socio-demographic, psychological and clinical data from approximately 24,000 adult volunteers across Scotland. Although data collection was cross-sectional, GS:SFHS became a prospective cohort due to of the ability to link to routine Electronic Health Record (EHR) data. Over 20,000 participants were selected for genotyping using a large genome-wide array.

Methods: GS:SFHS was analysed using genome-wide association studies (GWAS) to test the effects of a large spectrum of variants, imputed using the Haplotype Research Consortium (HRC) dataset, on medically relevant traits measured directly or obtained from EHRs. The HRC dataset is the largest available haplotype reference panel for imputation of variants in populations of European ancestry and allows investigation of variants with low minor allele frequencies within the entire GS:SFHS genotyped cohort.

Results: Genome-wide associations were run on 20,032 individuals using both genotyped and HRC imputed data. We present results for a range of well-studied quantitative traits obtained from clinic visits and for serum urate measures obtained from data linkage to EHRs collected by the Scottish National Health Service. Results replicated known associations and additionally reveal novel findings, mainly with rare variants, validating the use of the HRC imputation panel. For example, we identified two new associations with fasting glucose at variants near to Y_RNA and WDR4 and four new associations with heart rate at SNPs within CSMD1 and ASPH, upstream of HTR1F and between PROKR2 and GPCPD1. All were driven by rare variants (minor allele frequencies in the range of 0.08-1%). Proof of principle for use of EHRs was verification of the highly significant association of urate levels with the well-established urate transporter SLC2A9.

Conclusions: GS:SFHS provides genetic data on over 20,000 participants alongside a range of phenotypes as well as linkage to National Health Service laboratory and clinical records. We have shown that the combination of deeper genotype imputation and extended phenotype availability make GS:SFHS an attractive resource to carry out association studies to gain insight into the genetic architecture of complex traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-017-0414-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339960PMC
March 2017

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Nat Genet 2015 Nov 28;47(11):1294-1303. Epub 2015 Sep 28.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661791PMC
November 2015

How does selfing affect the dynamics of selfish transposable elements?

Mob DNA 2012 Mar 7;3. Epub 2012 Mar 7.

LEGS, CNRS UPR9034, IDEEV FR3284, Avenue de la terrasse, Bat 13, 91198 Gif-sur-Yvette, France.

Background: Many theoretical models predicting the dynamics of transposable elements (TEs) in genomes, populations, and species have already been proposed. However, most of them only focus on populations of sexual diploid individuals, and TE dynamics in populations partly composed by autogamous individuals remains poorly investigated. To estimate the impact of selfing on TE dynamics, the short- and long-term evolution of TEs was simulated in outcrossing populations with various proportions of selfing individuals.

Results: Selfing has a deep impact on TE dynamics: the higher the selfing rate, the lower the probability of invasion. Already known non-equilibrium dynamics (complete loss, domestication, cyclical invasion of TEs) can all be described whatever the mating system. However, their pattern and their respective frequencies greatly depend on the selfing rate. For instance, in cyclical dynamics resulting from interactions between autonomous and non-autonomous copies, cycles are faster when the selfing rate increases. Interestingly, an abrupt change in the mating system from sexuality to complete asexuality leads to the loss of all the elements over a few hundred generations. In general, for intermediate selfing rates, the transposition activity remains maintained.

Conclusions: Our theoretical results evidence that a clear and systematic contrast in TE content according to the mating system is expected, with a smooth transition for intermediate selfing rates. Several parameters impact the TE copy number, and all dynamics described in allogamous populations can be also observed in partly autogamous species. This study thus provides new insights to understand the complex signal from empirical comparison of closely related species with different mating systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1759-8753-3-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395816PMC
March 2012

The struggle for life of the genome's selfish architects.

Biol Direct 2011 Mar 17;6:19. Epub 2011 Mar 17.

Laboratoire Evolution, Génomes, Spéciation, CNRS UPR9034/Université Paris-Sud, Gif-sur-Yvette, France.

Unlabelled: Transposable elements (TEs) were first discovered more than 50 years ago, but were totally ignored for a long time. Over the last few decades they have gradually attracted increasing interest from research scientists. Initially they were viewed as totally marginal and anecdotic, but TEs have been revealed as potentially harmful parasitic entities, ubiquitous in genomes, and finally as unavoidable actors in the diversity, structure, and evolution of the genome. Since Darwin's theory of evolution, and the progress of molecular biology, transposable elements may be the discovery that has most influenced our vision of (genome) evolution. In this review, we provide a synopsis of what is known about the complex interactions that exist between transposable elements and the host genome. Numerous examples of these interactions are provided, first from the standpoint of the genome, and then from that of the transposable elements. We also explore the evolutionary aspects of TEs in the light of post-Darwinian theories of evolution.

Reviewers: This article was reviewed by Jerzy Jurka, Jürgen Brosius and I. King Jordan. For complete reports, see the Reviewers' reports section.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1745-6150-6-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072357PMC
March 2011

Long-term evolution of transposable elements.

Proc Natl Acad Sci U S A 2007 Dec 26;104(49):19375-80. Epub 2007 Nov 26.

Laboratoire Evolution, Génomes, et Spéciation, Avenue de la Terrasse, Bâtiment 13, 91198 Gif-sur-Yvette Cedex, France.

Transposable elements are often considered parasitic DNA sequences, able to invade the genome of their host thanks to their self-replicating ability. This colonization process has been extensively studied, both theoretically and experimentally, but their long-term coevolution with the genomes is still poorly understood. In this work, we aim to challenge previous population genetics models by considering features of transposable elements as quantitative, rather than discrete, variables. We also describe more realistic transposable element dynamics by accounting for the variability of the insertion effect, from deleterious to adaptive, as well as mutations leading to a loss of transposition activity and to nonautonomous copies. Individual-based simulations of the behavior of a transposable-element family over several thousand generations show different ways in which active or inactive copies can be maintained for a very long time. Results reveal an unexpected impact of genetic drift on the "junk DNA" content of the genome and strongly question the likelihood of the sustainable long-term stable transposition-selection equilibrium on which numerous previous works were based.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0705238104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148297PMC
December 2007
-->