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1.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Landt, Margarita CT Slof-Op t | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O'Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2014;19(10):1085-1094.
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
doi:10.1038/mp.2013.187
PMCID: PMC4325090  PMID: 24514567
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
2.  Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants 
Nature Communications  2014;5:5345.
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.
Isolated populations can increase power to detect low frequency and rare risk variants associated with complex phenotypes. Here, the authors identify variants associated with haematological traits in two isolated Greek populations that would be difficult to detect in the general population, due to their low frequency.
doi:10.1038/ncomms6345
PMCID: PMC4242463  PMID: 25373335
3.  Using ancestry-informative markers to identify fine structure across 15 populations of European origin 
European Journal of Human Genetics  2014;22(10):1190-1200.
The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5% we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia.
doi:10.1038/ejhg.2014.1
PMCID: PMC4169539  PMID: 24549058
population stratification; AIMs; principal component analysis
4.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Slof-Op t Landt, Margarita CT | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O’Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2010;16(9):10.1038/mp.2010.107.
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
doi:10.1038/mp.2010.107
PMCID: PMC3859494  PMID: 21079607
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
5.  Genome-wide meta-analysis of common variant differences between men and women 
Boraska, Vesna | Jerončić, Ana | Colonna, Vincenza | Southam, Lorraine | Nyholt, Dale R. | William Rayner, Nigel | Perry, John R.B. | Toniolo, Daniela | Albrecht, Eva | Ang, Wei | Bandinelli, Stefania | Barbalic, Maja | Barroso, Inês | Beckmann, Jacques S. | Biffar, Reiner | Boomsma, Dorret | Campbell, Harry | Corre, Tanguy | Erdmann, Jeanette | Esko, Tõnu | Fischer, Krista | Franceschini, Nora | Frayling, Timothy M. | Girotto, Giorgia | Gonzalez, Juan R. | Harris, Tamara B. | Heath, Andrew C. | Heid, Iris M. | Hoffmann, Wolfgang | Hofman, Albert | Horikoshi, Momoko | Hua Zhao, Jing | Jackson, Anne U. | Hottenga, Jouke-Jan | Jula, Antti | Kähönen, Mika | Khaw, Kay-Tee | Kiemeney, Lambertus A. | Klopp, Norman | Kutalik, Zoltán | Lagou, Vasiliki | Launer, Lenore J. | Lehtimäki, Terho | Lemire, Mathieu | Lokki, Marja-Liisa | Loley, Christina | Luan, Jian'an | Mangino, Massimo | Mateo Leach, Irene | Medland, Sarah E. | Mihailov, Evelin | Montgomery, Grant W. | Navis, Gerjan | Newnham, John | Nieminen, Markku S. | Palotie, Aarno | Panoutsopoulou, Kalliope | Peters, Annette | Pirastu, Nicola | Polašek, Ozren | Rehnström, Karola | Ripatti, Samuli | Ritchie, Graham R.S. | Rivadeneira, Fernando | Robino, Antonietta | Samani, Nilesh J. | Shin, So-Youn | Sinisalo, Juha | Smit, Johannes H. | Soranzo, Nicole | Stolk, Lisette | Swinkels, Dorine W. | Tanaka, Toshiko | Teumer, Alexander | Tönjes, Anke | Traglia, Michela | Tuomilehto, Jaakko | Valsesia, Armand | van Gilst, Wiek H. | van Meurs, Joyce B.J. | Smith, Albert Vernon | Viikari, Jorma | Vink, Jacqueline M. | Waeber, Gerard | Warrington, Nicole M. | Widen, Elisabeth | Willemsen, Gonneke | Wright, Alan F. | Zanke, Brent W. | Zgaga, Lina | Boehnke, Michael | d'Adamo, Adamo Pio | de Geus, Eco | Demerath, Ellen W. | den Heijer, Martin | Eriksson, Johan G. | Ferrucci, Luigi | Gieger, Christian | Gudnason, Vilmundur | Hayward, Caroline | Hengstenberg, Christian | Hudson, Thomas J. | Järvelin, Marjo-Riitta | Kogevinas, Manolis | Loos, Ruth J.F. | Martin, Nicholas G. | Metspalu, Andres | Pennell, Craig E. | Penninx, Brenda W. | Perola, Markus | Raitakari, Olli | Salomaa, Veikko | Schreiber, Stefan | Schunkert, Heribert | Spector, Tim D. | Stumvoll, Michael | Uitterlinden, André G. | Ulivi, Sheila | van der Harst, Pim | Vollenweider, Peter | Völzke, Henry | Wareham, Nicholas J. | Wichmann, H.-Erich | Wilson, James F. | Rudan, Igor | Xue, Yali | Zeggini, Eleftheria
Human Molecular Genetics  2012;21(21):4805-4815.
The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
doi:10.1093/hmg/dds304
PMCID: PMC3471397  PMID: 22843499
6.  The effect of genome-wide association scan quality control on imputation outcome for common variants 
Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.
doi:10.1038/ejhg.2010.242
PMCID: PMC3083623  PMID: 21267008
genome-wide association study; imputation; quality control; single nucleotide polymorphism
7.  Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations 
American Journal of Epidemiology  2009;170(5):537-545.
For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.
doi:10.1093/aje/kwp145
PMCID: PMC2732984  PMID: 19602701
Bayes theorem; diabetes mellitus, type 2; meta-analysis; models, genetic; polymorphism, genetic; population characteristics
8.  Underlying genetic models of inheritance in established type 2 diabetes associations 
American journal of epidemiology  2009;170(5):537-545.
For most associations of common polymorphisms with common diseases, the genetic model of inheritance is unknown. We extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations for type 2 diabetes. For 13 polymorphisms, the data fit very well to an additive model, for 4 polymorphisms the data were consistent with either an additive or dominant model, and for 2 polymorphisms with an additive or recessive model of inheritance for the diabetes risk allele. Results were robust to using different priors and after excluding data where index polymorphisms had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that are very similar to those previously reported based on fixed or random effects models, but uncertainty about several of the effects was substantially larger. We also examined the extent of between-study heterogeneity in the genetic model and found generally small values of the between-study deviation for the genetic model parameter. Heterosis could not be excluded in 4 SNPs. Information on the genetic model of robustly replicated GWA-derived association signals may be useful for predictive modeling, and for designing biological and functional experiments.
doi:10.1093/aje/kwp145
PMCID: PMC2732984  PMID: 19602701
9.  Association of a functional microsatellite within intron 1 of the BMP5 gene with susceptibility to osteoarthritis 
BMC Medical Genetics  2009;10:141.
Background
In a previous study carried out by our group, the genotyping of 36 microsatellite markers from within a narrow interval of chromosome 6p12.3-q13 generated evidence for linkage and for association to female hip osteoarthritis (OA), with the most compelling association found for a marker within intron 1 of the bone morphogenetic protein 5 gene (BMP5). In this study, we aimed to further categorize the association of variants within intron 1 of BMP5 with OA through an expanded genetic association study of the intron and subsequent functional analysis of associated polymorphisms.
Methods
We genotyped 18 common polymorphisms including 8 microsatellites and 9 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion (INDEL) from within highly conserved regions between human and mouse within intron 1 of BMP5. These markers were then tested for association to OA by a two-stage approach in which the polymorphisms were initially genotyped in a case-control cohort comprising 361 individuals with associated polymorphisms (P ≤ 0.05) then genotyped in a second case-control cohort comprising 1185 individuals.
Results
Two BMP5 intron 1 polymorphisms demonstrated association in the combined case-control cohort of 1546 individuals (765 cases and 781 controls): microsatellite D6S1276 (P = 0.018) and SNP rs921126 (P = 0.013). Functional analyses in osteoblastic, chondrocytic, and adipocytic cell lines indicated that allelic variants of D6S1276 have significant effects on the transcriptional activity of the BMP5 promoter in vitro.
Conclusion
Variability in gene expression of BMP5 may be an important contributor to OA genetic susceptibility.
doi:10.1186/1471-2350-10-141
PMCID: PMC2807860  PMID: 20021689
10.  No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls 
Annals of the Rheumatic Diseases  2012;72(1):136-139.
Objectives
Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated.
Methods
The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study.
Results
Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study.
Conclusions
We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.
doi:10.1136/annrheumdis-2012-201932
PMCID: PMC3551219  PMID: 22984172
Gene Polymorphism; Osteoarthritis; Pharmacogenetics
11.  Replication of Established Common Genetic Variants for Adult BMI and Childhood Obesity in Greek Adolescents: The TEENAGE Study 
Annals of Human Genetics  2013;77(3):268-274.
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/m2/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.
doi:10.1111/ahg.12012
PMCID: PMC3652032  PMID: 23347264
Obesity; BMI; common genetic variants; adolescents
12.  Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data 
Annals of the Rheumatic Diseases  2012;72(6):935-941.
Objectives
Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale.
Methods
We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls.
Results
We found significant overlap between osteoarthritis and height (p=3.3×10−5 for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10−5). As expected, this signal was attenuated when we adjusted for BMI.
Conclusions
We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.
doi:10.1136/annrheumdis-2012-202081
PMCID: PMC3664369  PMID: 22956599
Osteoarthritis; Gene Polymorphism; Epidemiology
14.  A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates 
Nature Communications  2013;4:2872.
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.
Isolated populations may empower genetic association studies of complex traits. Here, the authors identify a rare cardioprotective APOC3 variant in a Greek population isolate and highlight the value of using population isolates to detect rare variants that confer disease risk.
doi:10.1038/ncomms3872
PMCID: PMC3905724  PMID: 24343240
15.  A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans 
Nature Communications  2014;5:4871.
The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3 gene strongly associated with plasma triglyceride levels.
doi:10.1038/ncomms5871
PMCID: PMC4167609  PMID: 25225788
16.  A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip 
Annals of the Rheumatic Diseases  2013;73(12):2130-2136.
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.
doi:10.1136/annrheumdis-2012-203114
PMCID: PMC4251181  PMID: 23989986
Epidemiology; Gene Polymorphism; Osteoarthritis

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