Publications by authors named "Kalliope Panoutsopoulou"

42 Publications

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

Clin Orthop Relat Res 2019 02;477(2):297-309

S. J. MacInnes, K. Shah, J. M. Wilkinson, Department of Oncology and Metabolism, University of Sheffield, The Medical School, Sheffield, UK K. Hatzikotoulas, I. Tachmazidou, K. Panoutsopoulou, E. Zeggini, Wellcome Trust Sanger Institute, Cambridge, UK A. M. Fenstad, H. Dale, The Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway L. Southam, Wellcome Trust Centre for Human Genetics, Oxford, UK G. Hallan, O. Furnes, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway.

Background: Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown.

Questions/purposes: We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis.

Methods: The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken.

Results: Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ≤ 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ≤ 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ≤ 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ≤ 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10).

Conclusions: We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease.

Clinical Relevance: The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.
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http://dx.doi.org/10.1097/01.blo.0000533629.49193.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370091PMC
February 2019

Erratum to: The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

Clin Orthop Relat Res 2019 03;477(3):668

S. J. MacInnes, K. Shah, J. M. Wilkinson, Department of Oncology and Metabolism, University of Sheffield, The Medical School, Sheffield, UK K. Hatzikotoulas, I. Tachmazidou, K. Panoutsopoulou, E. Zeggini, Wellcome Trust Sanger Institute, Cambridge, UK A. M. Fenstad, H. Dale, The Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway L. Southam, Wellcome Trust Centre for Human Genetics, Oxford, UK G. Hallan, O. Furnes, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway.

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http://dx.doi.org/10.1097/CORR.0000000000000421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382182PMC
March 2019

Quality Control of Common and Rare Variants.

Methods Mol Biol 2018 ;1793:25-36

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, Cambridgeshire, United Kingdom.

Thorough data quality control (QC) is a key step to the success of high-throughput genotyping approaches. Following extensive research several criteria and thresholds have been established for data QC at the sample and variant level. Sample QC is aimed at the identification and removal (when appropriate) of individuals with (1) low call rate, (2) discrepant sex or other identity-related information, (3) excess genome-wide heterozygosity and homozygosity, (4) relations to other samples, (5) ethnicity differences, (6) batch effects, and (7) contamination. Variant QC is aimed at identification and removal or refinement of variants with (1) low call rate, (2) call rate differences by phenotypic status, (3) gross deviation from Hardy-Weinberg Equilibrium (HWE), (4) bad genotype intensity plots, (5) batch effects, (6) differences in allele frequencies with published data sets, (7) very low minor allele counts (MAC), (8) low imputation quality score, (9) low variant quality score log-odds, and (10) few or low quality reads.
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http://dx.doi.org/10.1007/978-1-4939-7868-7_3DOI Listing
February 2019

Key Concepts in Genetic Epidemiology.

Methods Mol Biol 2018 ;1793:7-24

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, Cambridgeshire, United Kingdom.

Genetic epidemiology is a discipline closely allied to traditional epidemiology that deals with the analysis of the familial distribution of traits. It emerged in the mid-1980s bringing together approaches and techniques developed in mathematical and quantitative genetics, medical and population genetics, statistics and epidemiology. The purpose of this chapter is to familiarize the reader with key concepts in genetic epidemiology as applied at present to unveil the familial and genetic determinants of disease and the joint effects of genes and environmental exposures.
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http://dx.doi.org/10.1007/978-1-4939-7868-7_2DOI Listing
February 2019

A novel variant in is associated with osteoarthritis.

Ann Rheum Dis 2018 04 7;77(4):620-623. Epub 2018 Feb 7.

Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

Objectives: Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date.

Methods: We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR.

Results: We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in , which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes.

Conclusions: We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.
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http://dx.doi.org/10.1136/annrheumdis-2017-211848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890630PMC
April 2018

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Am J Hum Genet 2017 Jun 25;100(6):865-884. Epub 2017 May 25.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital NHS Trust, Middlesex UB1 3EU, UK.

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.
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http://dx.doi.org/10.1016/j.ajhg.2017.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473732PMC
June 2017

Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis.

Ann Rheum Dis 2017 Jul 14;76(7):1199-1206. Epub 2016 Dec 14.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Objective: Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA.

Methods: A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage.

Results: We report suggestive evidence (p<5×10) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the gene (rs754106, p=1.49×10, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between and (rs6766414, p=3.13×10, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10).

Conclusions: Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.
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http://dx.doi.org/10.1136/annrheumdis-2016-210373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530347PMC
July 2017

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Nat Genet 2016 11 26;48(11):1303-1312. Epub 2016 Sep 26.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.
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http://dx.doi.org/10.1038/ng.3668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5279872PMC
November 2016

Genome-wide associations for birth weight and correlations with adult disease.

Nature 2016 10 28;538(7624):248-252. Epub 2016 Sep 28.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R = -0.22, P = 5.5 × 10), T2D (R = -0.27, P = 1.1 × 10) and coronary artery disease (R = -0.30, P = 6.5 × 10). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
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http://dx.doi.org/10.1038/nature19806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164934PMC
October 2016

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

PLoS Genet 2015 Oct 1;11(10):e1005378. Epub 2015 Oct 1.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
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http://dx.doi.org/10.1371/journal.pgen.1005378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591371PMC
October 2015

A Bayesian Approach to the Overlap Analysis of Epidemiologically Linked Traits.

Genet Epidemiol 2015 Dec 28;39(8):624-34. Epub 2015 Sep 28.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.

Diseases often cooccur in individuals more often than expected by chance, and may be explained by shared underlying genetic etiology. A common approach to genetic overlap analyses is to use summary genome-wide association study data to identify single-nucleotide polymorphisms (SNPs) that are associated with multiple traits at a selected P-value threshold. However, P-values do not account for differences in power, whereas Bayes' factors (BFs) do, and may be approximated using summary statistics. We use simulation studies to compare the power of frequentist and Bayesian approaches with overlap analyses, and to decide on appropriate thresholds for comparison between the two methods. It is empirically illustrated that BFs have the advantage over P-values of a decreasing type I error rate as study size increases for single-disease associations. Consequently, the overlap analysis of traits from different-sized studies encounters issues in fair P-value threshold selection, whereas BFs are adjusted automatically. Extensive simulations show that Bayesian overlap analyses tend to have higher power than those that assess association strength with P-values, particularly in low-power scenarios. Calibration tables between BFs and P-values are provided for a range of sample sizes, as well as an approximation approach for sample sizes that are not in the calibration table. Although P-values are sometimes thought more intuitive, these tables assist in removing the opaqueness of Bayesian thresholds and may also be used in the selection of a BF threshold to meet a certain type I error rate. An application of our methods is used to identify variants associated with both obesity and osteoarthritis.
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http://dx.doi.org/10.1002/gepi.21919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832282PMC
December 2015

Investigation of association between hip osteoarthritis susceptibility loci and radiographic proximal femur shape.

Arthritis Rheumatol 2015 May;67(8):2076-84

University of Manchester, Manchester, UK.

Objective: To test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits.

Methods: We used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome-wide association study. We built 3 SSMs capturing the shape variation of the OA-unaffected proximal femur in the entire mixed-sex cohort and for male/female-stratified cohorts. We selected 41 candidate single-nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype-phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes.

Results: The univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed-sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed-sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA.

Conclusion: These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.
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http://dx.doi.org/10.1002/art.39186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864451PMC
May 2015

Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants.

Nat Commun 2014 Nov 6;5:5345. Epub 2014 Nov 6.

Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 17671, Greece.

Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10(-26)). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10(-36)). We demonstrate significant power gains in detecting medical trait associations.
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http://dx.doi.org/10.1038/ncomms6345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242463PMC
November 2014

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Hum Mol Genet 2015 Feb 3;24(4):1155-68. Epub 2014 Oct 3.

MRC Integrative Epidemiology Unit .

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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http://dx.doi.org/10.1093/hmg/ddu510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447786PMC
February 2015

Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.

J Med Genet 2014 Sep 23;51(9):596-604. Epub 2014 Jul 23.

Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.

Background: Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II).

Methods: Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage.

Results: Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage.

Conclusions: We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.
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http://dx.doi.org/10.1136/jmedgenet-2014-102478DOI Listing
September 2014

Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty.

Hum Mol Genet 2014 Aug 25;23(16):4452-64. Epub 2014 Apr 25.

Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catelonia, Spain Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Barcelona, Catalonia, Spain Genes and genomes, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain and.

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
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http://dx.doi.org/10.1093/hmg/ddu150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168307PMC
August 2014

Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies.

Arthritis Rheumatol 2014 Apr;66(4):940-9

Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.

Objective: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.

Methods: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.

Results: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.

Conclusion: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
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http://dx.doi.org/10.1002/art.38300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660891PMC
April 2014

Revisiting the thrifty gene hypothesis via 65 loci associated with susceptibility to type 2 diabetes.

Am J Hum Genet 2014 Feb 9;94(2):176-85. Epub 2014 Jan 9.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, UK. Electronic address:

We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the thrifty gene hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles.
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http://dx.doi.org/10.1016/j.ajhg.2013.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928649PMC
February 2014

A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates.

Nat Commun 2013 ;4:2872

Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (<0.05% frequency) in outbred European populations. The increased frequency of R19X enables discovery of this lipid traits signal at genome-wide significance in a small sample size. This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance.
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http://dx.doi.org/10.1038/ncomms3872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905724PMC
October 2014

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

Ann Rheum Dis 2014 Dec 29;73(12):2130-6. Epub 2013 Aug 29.

Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.

Methods: We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.

Results: We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).

Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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http://dx.doi.org/10.1136/annrheumdis-2012-203114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251181PMC
December 2014

In search of low-frequency and rare variants affecting complex traits.

Hum Mol Genet 2013 Oct 6;22(R1):R16-21. Epub 2013 Aug 6.

The allelic architecture of complex traits is likely to be underpinned by a combination of multiple common frequency and rare variants. Targeted genotyping arrays and next-generation sequencing technologies at the whole-genome sequencing (WGS) and whole-exome scales (WES) are increasingly employed to access sequence variation across the full minor allele frequency (MAF) spectrum. Different study design strategies that make use of diverse technologies, imputation and sample selection approaches are an active target of development and evaluation efforts. Initial insights into the contribution of rare variants in common diseases and medically relevant quantitative traits point to low-frequency and rare alleles acting either independently or in aggregate and in several cases alongside common variants. Studies conducted in population isolates have been successful in detecting rare variant associations with complex phenotypes. Statistical methodologies that enable the joint analysis of rare variants across regions of the genome continue to evolve with current efforts focusing on incorporating information such as functional annotation, and on the meta-analysis of these burden tests. In addition, population stratification, defining genome-wide statistical significance thresholds and the design of appropriate replication experiments constitute important considerations for the powerful analysis and interpretation of rare variant association studies. Progress in addressing these emerging challenges and the accrual of sufficiently large data sets are poised to help the field of complex trait genetics enter a promising era of discovery.
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http://dx.doi.org/10.1093/hmg/ddt376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782074PMC
October 2013

The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a Mendelian randomisation study.

Ann Rheum Dis 2014 Dec 6;73(12):2082-6. Epub 2013 Aug 6.

Department of Twin Research, King's College London, St Thomas' Hospital, London, UK Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.

Objective: Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information.

Methods: 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA.

Results: In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA.

Conclusions: Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA.
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http://dx.doi.org/10.1136/annrheumdis-2013-203772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251538PMC
December 2014

Advances in osteoarthritis genetics.

J Med Genet 2013 Nov 18;50(11):715-24. Epub 2013 Jul 18.

Department of Human Genetics, Wellcome Trust Sanger Institute, Cambridgeshire, UK.

Osteoarthritis (OA), the most common form of arthritis, is a highly debilitating disease of the joints and can lead to severe pain and disability. There is no cure for OA. Current treatments often fail to alleviate its symptoms leading to an increased demand for joint replacement surgery. Previous epidemiological and genetic research has established that OA is a multifactorial disease with both environmental and genetic components. Over the past 6 years, a candidate gene study and several genome-wide association scans (GWAS) in populations of Asian and European descent have collectively established 15 loci associated with knee or hip OA that have been replicated with genome-wide significance, shedding some light on the aetiogenesis of the disease. All OA associated variants to date are common in frequency and appear to confer moderate to small effect sizes. Some of the associated variants are found within or near genes with clear roles in OA pathogenesis, whereas others point to unsuspected, less characterised pathways. These studies have also provided further evidence in support of the existence of ethnic, sex, and joint specific effects in OA and have highlighted the importance of expanded and more homogeneous phenotype definitions in genetic studies of OA.
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http://dx.doi.org/10.1136/jmedgenet-2013-101754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812881PMC
November 2013

Bioanalysis young investigator: award 2013.

Bioanalysis 2013 Jun;5(11):1341-5

Nutrition & Food Science Department, XaRTA, INSA. Pharmacy School, University of Barcelona. Av. Joan XXIII s/n, 08028 Barcelona, Spain.

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http://dx.doi.org/10.4155/bio.13.96DOI Listing
June 2013

Replication of established common genetic variants for adult BMI and childhood obesity in Greek adolescents: the TEENAGE study.

Ann Hum Genet 2013 May 24;77(3):268-74. Epub 2013 Jan 24.

Harokopio University of Athens, Department of Nutrition and Dietetics, 17671 Athens, Greece.

Multiple genetic loci have been associated with body mass index (BMI) and obesity. The aim of this study was to investigate the effects of established adult BMI and childhood obesity loci in a Greek adolescent cohort. For this purpose, 34 variants were selected for investigation in 707 (55.9% females) adolescents of Greek origin aged 13.42 ± 0.88 years. Cumulative effects of variants were assessed by calculating a genetic risk score (GRS-34) for each subject. Variants at the FTO, TMEM18, FAIM2, RBJ, ZNF608 and QPCTL loci yielded nominal evidence for association with BMI and/or overweight risk (p < 0.05). Variants at TFAP2B and NEGR1 loci showed nominal association (p < 0.05) with BMI and/or overweight risk in males and females respectively. Even though we did not detect any genome-wide significant associations, 27 out of 34 variants yielded directionally consistent effects with those reported by large-scale meta-analyses (binomial sign p = 0.0008). The GRS-34 was associated with both BMI (beta = 0.17 kg/m(2) /allele; p < 0.001) and overweight risk (OR = 1.09/allele; 95% CI: 1.04-1.16; p = 0.001). In conclusion, we replicate associations of established BMI and childhood obesity variants in a Greek adolescent cohort and confirm directionally consistent effects for most of them.
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http://dx.doi.org/10.1111/ahg.12012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652032PMC
May 2013
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