Publications by authors named "Thibaud Boutin"

37 Publications

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

Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants.

Commun Biol 2020 12 11;3(1):762. Epub 2020 Dec 11.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH42XU, UK.

Corneal resistance factor (CRF) is altered during corneal diseases progression. Genome-wide-association studies (GWAS) indicated potential CRF and disease genetics overlap. Here, we characterise 135 CRF loci following GWAS in 76029 UK Biobank participants. Enrichment of extra-cellular matrix gene-sets, genetic correlation with corneal thickness (70% (SE = 5%)), reported keratoconus risk variants at 13 loci, all support relevance to corneal stroma biology. Fine-mapping identifies a subset of 55 highly likely causal variants, 91% of which are non-coding. Genomic features enrichments, using all associated variants, also indicate prominent regulatory causal role. We newly established open chromatin landscapes in two widely-used human cornea immortalised cell lines using ATAC-seq. Variants associated with CRF were significantly enriched in regulatory regions from the corneal stroma-derived cell line and enrichment increases to over 5 fold for variants prioritised by fine-mapping-including at GAS7, SMAD3 and COL6A1 loci. Our analysis generates many hypotheses for future functional validation of aetiological mechanisms.
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http://dx.doi.org/10.1038/s42003-020-01497-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732848PMC
December 2020

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.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611474PMC
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.
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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.
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http://dx.doi.org/10.1371/journal.pgen.1008785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337286PMC
July 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

An epigenome-wide association study of sex-specific chronological ageing.

Genome Med 2019 12 31;12(1). Epub 2019 Dec 31.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.

Background: Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years.

Methods: Linear regression models were applied, with stringent genome-wide significance thresholds (p < 3.6 × 10) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds.

Results: Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10, an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = - 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction.

Conclusion: The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.
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http://dx.doi.org/10.1186/s13073-019-0693-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938636PMC
December 2019

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

Genome-Wide Analysis Identifies Two Susceptibility Loci for Positive Thyroid Peroxidase and Thyroglobulin Antibodies.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Medical Biology, University of Split, School of Medicine, Split, Croatia.

Introduction: Thyroid peroxidase (TPO) and thyroglobulin (Tg) are main components of the thyroid gland and play an essential role in thyroid hormone synthesis. The development of antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) is the major diagnostic hallmark and early indicator of autoimmune thyroid disease. TPOAb and TgAb are under strong genetic influence; however, genetic factors that determine thyroid antibody positivity are largely unknown.

Materials And Methods: To identify novel loci associated with TPOAb and/or TgAb positivity, we performed a genome-wide meta-analysis in a total of 2613 individuals from Croatia. Participants with elevated plasma TPOAb and/or TgAb were defined as cases (N = 619) and those with TPOAb and TgAb within reference values were defined as controls (N = 1994).

Results: We identified 2 novel loci, of which 1 is located within the YES1 gene (rs77284350, P = 1.50 × 10-8), and the other resides within the IRF8 gene (rs16939945, P = 5.04 × 10-8).

Conclusions: Although the observed variants were associated with TPOAb and TgAb positivity for the first time, both YES1 and IRF8 were previously linked to susceptibility to other autoimmune diseases, and represent plausible biological candidates. This study adds to the knowledge of genetics underlying thyroid antibodies and provides a good basis for further research.
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http://dx.doi.org/10.1210/clinem/dgz239DOI Listing
March 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.
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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.
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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.
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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.
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http://dx.doi.org/10.1038/s41467-019-10155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494888PMC
May 2019

Genetic Variants in the Gene Are Associated with Thyroglobulin Plasma Level in Healthy Individuals.

Thyroid 2019 06 13;29(6):886-893. Epub 2019 May 13.

1 Department of Medical Biology; School of Medicine; University of Split, Split, Croatia.

Thyroglobulin (Tg) is a 660 kDa iodoglycoprotein that serves as a scaffold for thyroid hormone synthesis. Although a twin study showed that variability of serum Tg levels has a substantial genetic basis, no genome-wide association study (GWAS) of serum/plasma Tg levels has been performed to date. The aim of this study was to identify genetic variants associated with plasma Tg levels among healthy individuals. A GWAS was conducted on two Croatian cohorts, and a combined analysis was performed. The analyses included 1094 individuals. A total of 7,597,379 variants, imputed using the 1000 Genomes reference panel, were analyzed for association. GWAS was performed under an additive model, controlling for age, sex, and relatedness within each data set. Combined analysis was conducted using the inverse-variance fixed-effects method. Sixteen variants located on chromosome 3, within the gene, reached genome-wide significance. The lead SNP was rs4012172 ( \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\usepackage{upgreek}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} $$p = 1.29 \times {10^{ - 10}}$$ \end{document} ), which explained 3.19% of the variance in Tg levels. belongs to the sialyltransferase protein family, which has a fundamental role in the synthesis of specific sialylated structures on various glycoproteins, including Tg. It is known that only immature Tg (poorly sialylated or desialylated) can be transferred to the bloodstream. A highly biologically plausible locus was identified that could have a role in the regulation of plasma Tg levels in healthy individuals.
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http://dx.doi.org/10.1089/thy.2018.0661DOI Listing
June 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.
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http://dx.doi.org/10.1038/s41467-019-09301-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437195PMC
March 2019

Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population.

J Hum Genet 2019 May 1;64(5):473-480. Epub 2019 Mar 1.

Department of Medical Biology, University of Split, School of Medicine, Šoltanska 2, Split, Croatia.

Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.
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http://dx.doi.org/10.1038/s10038-019-0586-4DOI Listing
May 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.
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http://dx.doi.org/10.1038/s41588-018-0303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365102PMC
January 2019

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Nat Genet 2018 10 17;50(10):1412-1425. Epub 2018 Sep 17.

Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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http://dx.doi.org/10.1038/s41588-018-0205-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284793PMC
October 2018

Genome-wide meta-analysis identifies novel loci associated with parathyroid hormone level.

Mol Med 2018 04 11;24(1):15. Epub 2018 Apr 11.

Department of Medical Biology, University of Split, School of Medicine, Šoltanska 2, Split, Croatia.

Background: Parathyroid hormone (PTH) is one of the principal regulators of calcium homeostasis. Although serum PTH level is mostly accounted by genetic factors, genetic background underlying PTH level is insufficiently known. Therefore, the aim of this study was to identify novel genetic variants associated with PTH levels.

Methods: We performed GWAS meta-analysis within two genetically isolated Croatian populations followed by replication analysis in a Croatian mainland population and we also combined results across all three analyzed populations. The analyses included 2596 individuals. A total of 7,411,206 variants, imputed using the 1000 Genomes reference panel, were analysed for the association. In addition, a sex-specific GWAS meta-analyses were performed.

Results: Polymorphisms with the lowest P-values were located on chromosome 4 approximately 84 kb of the 5' of RASGEF1B gene. The most significant SNP was rs11099476 (P = 1.15 × 10). Sex-specific analysis identified genome-wide significant association of the variant rs77178854, located within DPP10 gene in females only (P = 2.21 × 10). There were no genome-wide significant findings in the meta-analysis of males.

Conclusions: We identified two biologically plausible novel loci associated with PTH levels, providing us with further insights into the genetics of this complex trait.
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http://dx.doi.org/10.1186/s10020-018-0018-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016867PMC
April 2018

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Nat Commun 2018 05 14;9(1):1864. Epub 2018 May 14.

Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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http://dx.doi.org/10.1038/s41467-018-03646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951816PMC
May 2018

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

Circ Genom Precis Med 2018 05;11(5):e002037

Section of Computational Biomedicine (H.L.) and Section of Cardiovascular Medicine (E.J.B.), Department of Medicine, Boston University School of Medicine, MA. National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, MA (H.L., E.J.B.). Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.v.S., F.W.A.). Icelandic Heart Association, Kopavogur (A.V.S., V.G.). Faculty of Medicine, University of Iceland, Reykjavik (A.V.S., V.G.). Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine (N.A.B.) and McKusick-Nathans Institute of Genetic Medicine (D.E.A.), Johns Hopkins University School of Medicine, Baltimore, MD. William Harvey Research Institute (H.R.W., P.B.M.) and NIHR Barts Cardiovascular Research Unit (H.R.W., P.B.M.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom. Cardiovascular Health Research Unit, Department of Medicine (J.A.B., J.C.B., C.M.S.), Department of Biostatistics (K.M.R.), Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology (N.S.), Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services (B.M.P.), and Cardiovascular Health Research Unit, Department of Epidemiology (S.R.H.), University of Washington, Seattle. Center for Human Genetic Research (F. Radmanesh, J.R.) and Cardiovascular Research Center (P.L.H., L.-C.W., H.S.J., W.H., A.H., N.R.T., P.T.E., S.A.L.), Massachusetts General Hospital, Boston. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (L.-C.W., P.T.E., S.A.L.). Department of Cardiovascular Sciences, University of Leicester, United Kingdom (L.H., C.P.N., N.J.S.). NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom (L.H., C.P.N., N.J.S.). The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences (N.G., J.B.-J., O. Pedersen, T.H.), Laboratory of Experimental Cardiology (J.K.K.), and Department of Clinical Medicine, Faculty of Health and Medical Sciences (A.L.), University of Copenhagen, Denmark. Department of Medicine I, University Hospital Munich, Ludwig Maximilian's University Munich, Germany (M.M.-N., M.F.S., S.K.). Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany (K.S.). DZHK (German Cardiovascular Research Centre), Partner Site: Munich Heart Alliance, Germany (M.M.-N., M.F.S., A.P., T.M., S.K.). Institute of Genetic Epidemiology (M.M.-N., K.S.), Institute of Epidemiology II (A.P., M.W.), Research Unit of Molecular Epidemiology (M.W.), and Institute of Human Genetics (T.M.), Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine (T.B., J.M., C.H.) and Usher Institute of Population Health Sciences and Informatics (I.R.), University of Edinburgh, United Kingdom. University of Groningen, University Medical Center Groningen, Department of Cardiology, The Netherlands (N.V., R.A.d.B., P.v.d.M., P.v.d.H.). Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (H.J.L., Y.-D.I.C., J.Y., X.G., K.D.T., J.I.R.). Department of Clinical Epidemiology (R.L.-G., D.O.M.-K.) and Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center, The Netherlands. Department of Medical Informatics (M.E.v.d.B.), Human Genomics Facility (F. Rivadeneira), Human Genotyping Facility (A.U.), and Department of Epidemiology (M.E., B.H. Stricker), Erasmus MC, University Medical Center Rotterdam, The Netherlands. Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Germany (S.W., G.H., U.V.). DZHK (German Cardiovascular Research Centre), Partner Site Greifswald, Germany (S.W., H.V., S.B.F., U.V., M.D.). Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K.). Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences (L.-P.L., T.L.) and Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences (M.K.), University of Tampere, Finland. Department of Data Science (H.M.) and Physiology and Biophysics (J.G.W.), University of Mississippi Medical Center, Jackson. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD (T.B.H., L.J.L.). Division of Nephrology and Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City (M.L.). Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.). Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.). Medical Research Institute (J.M.C.) and Division of Population Health Sciences (B.H. Smith), Ninewells Hospital and Medical School, University of Dundee, United Kingdom. Department of Medical Informatics (J.A.K.) and Genetic Epidemiology Unit, Department of Epidemiology (C.M.v.D.), Erasmus MC, Rotterdam, The Netherlands. TCM Clinical Basis Institute, Zhejiang Chinese Medicine University, Hangzhou, China (Z.X., C.W.). Division of Cardiology, Department of Medicine, UPMC Heart and Vascular Institute, University of Pittsburgh, PA (J.W.M.). German Center for Diabetes Research, Neuherberg, Germany (A.P.). Institute of Human Genetics, Technische Universität München, Germany (T.M.). Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen (A.L.). Department of Clinical Experimental Research, Rigshospitalet, Denmark (A.L.). British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland (S.P.). Institute for Community Medicine (H.V.) and Department of Internal Medicine B (S.B.F., M.D.), University Medicine Greifswald, Germany. Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom (M.M., T.D.S.). Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands (M.L.B.). Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (M.P.). Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland (O.T.R.). Kaiser Permanente Washington Health Research Institute, Kaiser Foundation Health Plan of Washington, Seattle (B.M.P., S.R.H.). Faculty of Medicine, University of Split, Croatia (O. Polasek). Cardiogenetics Lab, Genetics and Molecular Cell Sciences Research Centre, Cardiovascular and Cell Sciences Institute, St George's, University of London, Cranmer Terrace, United Kingdom (B.P.P., Y.J.). Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands (F.W.A.). Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom (F.W.A.). Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, United Kingdom; CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio) and Department of Biochemistry, Maastricht University, The Netherlands (A.I.).

Background: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

Methods: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

Results: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

Conclusions: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
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http://dx.doi.org/10.1161/CIRCGEN.117.002037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951629PMC
May 2018

Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians.

Genomics 2019 07 18;111(4):737-743. Epub 2018 Apr 18.

Department of Medical Biology, University of Split, School of Medicine, Šoltanska 2, Split, Croatia. Electronic address:

Autoimmune thyroid diseases (AITD) are multifactorial endocrine diseases most frequently accompanied by Tg and TPO autoantibodies. Both antibodies have a higher prevalence in females and act under a strong genetic influence. To identify novel variants underlying thyroid antibody levels, we performed GWAS meta-analysis on the plasma levels of TgAb and TPOAb in three Croatian cohorts, as well as gender specific GWAS and a bivariate analysis. No significant association was detected with the level of TgAb and TPOAb in the meta-analysis of GWAS or bivariate results for all individuals. The bivariate analysis in females only revealed a genome-wide significant association for the locus near GRIN3A (rs4457391, P = 7.76 × 10). The same locus had borderline association with TPOAb levels in females (rs1935377, P = 8.58 × 10). In conclusion, we identified a novel gender specific locus associated with TgAb and TPOAb levels. Our findings provide a novel insight into genetic and gender differences associated with thyroid antibodies.
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http://dx.doi.org/10.1016/j.ygeno.2018.04.012DOI Listing
July 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.
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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.
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http://dx.doi.org/10.1038/s41467-017-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715013PMC
October 2017

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Nat Genet 2017 Jun 24;49(6):834-841. Epub 2017 Apr 24.

Institute of Genetics and Biophysics, CNR, Naples, Italy.

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
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http://dx.doi.org/10.1038/ng.3841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841952PMC
June 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.
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http://dx.doi.org/10.1186/s13073-017-0414-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339960PMC
March 2017
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