Search tips
Search criteria

Results 1-25 (59)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
1.  Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease 
Medici, Marco | Porcu, Eleonora | Pistis, Giorgio | Teumer, Alexander | Brown, Suzanne J. | Jensen, Richard A. | Rawal, Rajesh | Roef, Greet L. | Plantinga, Theo S. | Vermeulen, Sita H. | Lahti, Jari | Simmonds, Matthew J. | Husemoen, Lise Lotte N. | Freathy, Rachel M. | Shields, Beverley M. | Pietzner, Diana | Nagy, Rebecca | Broer, Linda | Chaker, Layal | Korevaar, Tim I. M. | Plia, Maria Grazia | Sala, Cinzia | Völker, Uwe | Richards, J. Brent | Sweep, Fred C. | Gieger, Christian | Corre, Tanguy | Kajantie, Eero | Thuesen, Betina | Taes, Youri E. | Visser, W. Edward | Hattersley, Andrew T. | Kratzsch, Jürgen | Hamilton, Alexander | Li, Wei | Homuth, Georg | Lobina, Monia | Mariotti, Stefano | Soranzo, Nicole | Cocca, Massimiliano | Nauck, Matthias | Spielhagen, Christin | Ross, Alec | Arnold, Alice | van de Bunt, Martijn | Liyanarachchi, Sandya | Heier, Margit | Grabe, Hans Jörgen | Masciullo, Corrado | Galesloot, Tessel E. | Lim, Ee M. | Reischl, Eva | Leedman, Peter J. | Lai, Sandra | Delitala, Alessandro | Bremner, Alexandra P. | Philips, David I. W. | Beilby, John P. | Mulas, Antonella | Vocale, Matteo | Abecasis, Goncalo | Forsen, Tom | James, Alan | Widen, Elisabeth | Hui, Jennie | Prokisch, Holger | Rietzschel, Ernst E. | Palotie, Aarno | Feddema, Peter | Fletcher, Stephen J. | Schramm, Katharina | Rotter, Jerome I. | Kluttig, Alexander | Radke, Dörte | Traglia, Michela | Surdulescu, Gabriela L. | He, Huiling | Franklyn, Jayne A. | Tiller, Daniel | Vaidya, Bijay | de Meyer, Tim | Jørgensen, Torben | Eriksson, Johan G. | O'Leary, Peter C. | Wichmann, Eric | Hermus, Ad R. | Psaty, Bruce M. | Ittermann, Till | Hofman, Albert | Bosi, Emanuele | Schlessinger, David | Wallaschofski, Henri | Pirastu, Nicola | Aulchenko, Yurii S. | de la Chapelle, Albert | Netea-Maier, Romana T. | Gough, Stephen C. L. | Meyer zu Schwabedissen, Henriette | Frayling, Timothy M. | Kaufman, Jean-Marc | Linneberg, Allan | Räikkönen, Katri | Smit, Johannes W. A. | Kiemeney, Lambertus A. | Rivadeneira, Fernando | Uitterlinden, André G. | Walsh, John P. | Meisinger, Christa | den Heijer, Martin | Visser, Theo J. | Spector, Timothy D. | Wilson, Scott G. | Völzke, Henry | Cappola, Anne | Toniolo, Daniela | Sanna, Serena | Naitza, Silvia | Peeters, Robin P. | Cotsapas, Chris
PLoS Genetics  2014;10(2):e1004123.
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10−8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10−8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10−6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10−4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10−7 and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10−5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10−3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
Author Summary
Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction.
PMCID: PMC3937134  PMID: 24586183
2.  Reactome - a curated knowledgebase of biological pathways: megakaryocytes and platelets 
The platelet field is undergoing a radical transformation from reductionist simplification to large scale integration. Following the era of simplification whereby biological processes were dissected at the molecular and atomic level, new technologies have now generated an overwhelming flow of information that can only be comprehended in an integrated approach. High throughput analyses of transcription and translation in megakaryocytes and platelets, individual analyses of membranes and secretory granules, the clustering of pathways for platelet activation and inhibition in signalosomes all add to a complexity that requires platforms for knowledge accumulation. Here we introduce Reactome, a curated knowledgebase of biological pathways with extensive coverage of pathways relevant to megakaryocytes, platelets and haemostasis. This resource is compared with other data resources for platelets, e.g. the Platelet Web.
PMCID: PMC3578965  PMID: 22985186
3.  Small effective population size and genetic homogeneity in the Val Borbera isolate 
Population isolates are a valuable resource for medical genetics because of their reduced genetic, phenotypic and environmental heterogeneity. Further, extended linkage disequilibrium (LD) allows accurate haplotyping and imputation. In this study, we use nuclear and mitochondrial DNA data to determine to what extent the geographically isolated population of the Val Borbera valley also presents features of genetic isolation. We performed a comparative analysis of population structure and estimated effective population size exploiting LD data. We also evaluated haplotype sharing through the analysis of segments of autozygosity. Our findings reveal that the valley has features characteristic of a genetic isolate, including reduced genetic heterogeneity and reduced effective population size. We show that this population has been subject to prolonged genetic drift and thus we expect many variants that are rare in the general population to reach significant frequency values in the valley, making this population suitable for the identification of rare variants underlying complex traits.
PMCID: PMC3522197  PMID: 22713810
genetic isolates; effective population size; linkage disequilibrium; mitochondrial DNA variation
4.  Ischaemic stroke is associated with the ABO locus: the Euroclot study 
Annals of neurology  2013;73(1):16-31.
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n=2,100 Stage 1) were examined in ischemic stroke (n=4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases 55,000 controls) was used for replication (Stage 3).
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. Most striking associations included SNP rs5985 with factor XIII activity (p=2.6×10-186), rs10665 with FVII (p = 2.4×10-47) and rs505922 in the ABO gene with both von Willebrand Factor (vWF p=4.7×10-57) and factor VIII (p=1.2×10-36). In Stage 2, the 23 independent SNPs were examined in stroke cases/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=0.066 (0.02) p = 0.001, a finding specific to large vessel and cardioembolic stroke (p = 0.001 and p = <0.001 respectively) but not seen with small vessel stroke (p=0.811).
ABO gene variants are associated with large vessel and cardioembolic stroke but not small vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
PMCID: PMC3582024  PMID: 23381943
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
5.  Human metabolic individuality in biomedical and pharmaceutical research 
Nature  2011;477(7362):10.1038/nature10354.
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 exhibit effect sizes that are unusually high for GWAS and account for 10-60% of metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn’s disease. Taken together our study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
PMCID: PMC3832838  PMID: 21886157
6.  Mapping cis- and trans-regulatory effects across multiple tissues in twins 
Nature genetics  2012;44(10):1084-1089.
Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many eQTL studies typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis-effect on expression cannot be accounted for by common cis-variants, a finding which exposes the contribution of low frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene and identify several replicating trans-variants which act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
PMCID: PMC3784328  PMID: 22941192
7.  A genomewide perspective of genetic variation in human metabolism 
Nature genetics  2009;42(2):137-141.
Serum metabolite concentrations provide a direct readout of biological processes in the human body, and are associated with disorders such as cardiovascular and metabolic diseases. Here we present a genome-wide association study with 163 metabolic traits using 1809 participants from the KORA population, followed up in the TwinsUK cohort with 422 participants. In eight out of nine replicated loci (FADS1, ELOVL2, ACADS, ACADM, ACADL, SPTLC3, ETFDH, SLC16A9) the genetic variant is located in or near enzyme or solute carrier coding genes, where the associating metabolic traits match the proteins’ function. Many of these loci are located in rate limiting steps of important enzymatic reactions. Use of metabolite concentration ratios as proxies for enzymatic reaction rates reduces the variance and yields robust statistical associations with p-values between 3×10−24 and 6.5×10−179. These loci explained 5.6% to 36.3% of the observed variance. For several loci, associations with clinically relevant parameters have previously been reported.
PMCID: PMC3773904  PMID: 20037589
8.  Variants near TERC are associated with mean telomere length. 
Nature genetics  2010;42(3):197-199.
We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 subjects and follow-up replication analyses in 9,492 and identified a locus on 3q26 encompassing the telomerase RNA component TERC, with compelling evidence for association (rs12696304, combined P value 3.72×10−14). Each copy of the minor allele of rs12696304 was associated with ≈75 base pairs shorter mean telomere length equivalent to ≈3.6 years of age-related attrition of mean telomere length.
PMCID: PMC3773906  PMID: 20139977
9.  Genome Wide Association Analysis of a Founder Population Identified TAF3 as a Gene for MCHC in Humans 
PLoS ONE  2013;8(7):e69206.
The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5–10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E–09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.
PMCID: PMC3729833  PMID: 23935956
10.  The Presence of Methylation Quantitative Trait Loci Indicates a Direct Genetic Influence on the Level of DNA Methylation in Adipose Tissue 
PLoS ONE  2013;8(2):e55923.
Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.
PMCID: PMC3576415  PMID: 23431366
11.  Genes Contributing to Pain Sensitivity in the Normal Population: An Exome Sequencing Study 
PLoS Genetics  2012;8(12):e1003095.
Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10−4). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.
Author Summary
Chronic widespread pain is a complex clinical problem. Identification of underlying genetic factors would shed light on the biology of pain and offer targets for novel therapies. We aimed to identify rare genetic variants in the normal population associated with pain sensation by performing exome sequencing on individuals who were more or less sensitive to heat pain. While we did not identify any single variants having large effect, we did observe major group differences between the sensitive and insensitive individuals. Network analysis suggested a role for the angiotensin pathway, which previous work in animal models has suggested is important in pain mediation. Our results cast light on the genetic factors underlying normal pain sensation in humans and the utility of exome analyses. It suggests that further exploration of the angiotensin pathway may reveal novel targets for the treatment of pain.
PMCID: PMC3527205  PMID: 23284290
12.  Variants in MTNR1B influence fasting glucose levels 
Prokopenko, Inga | Langenberg, Claudia | Florez, Jose C | Saxena, Richa | Soranzo, Nicole | Thorleifsson, Gudmar | Loos, Ruth J F | Manning, Alisa K | Jackson, Anne U | Aulchenko, Yurii | Potter, Simon C | Erdos, Michael R | Sanna, Serena | Hottenga, Jouke-Jan | Wheeler, Eleanor | Kaakinen, Marika | Lyssenko, Valeriya | Chen, Wei-Min | Ahmadi, Kourosh | Beckmann, Jacques S | Bergman, Richard N | Bochud, Murielle | Bonnycastle, Lori L | Buchanan, Thomas A | Cao, Antonio | Cervino, Alessandra | Coin, Lachlan | Collins, Francis S | Crisponi, Laura | de Geus, Eco J C | Dehghan, Abbas | Deloukas, Panos | Doney, Alex S F | Elliott, Paul | Freimer, Nelson | Gateva, Vesela | Herder, Christian | Hofman, Albert | Hughes, Thomas E | Hunt, Sarah | Illig, Thomas | Inouye, Michael | Isomaa, Bo | Johnson, Toby | Kong, Augustine | Krestyaninova, Maria | Kuusisto, Johanna | Laakso, Markku | Lim, Noha | Lindblad, Ulf | Lindgren, Cecilia M | McCann, Owen T | Mohlke, Karen L | Morris, Andrew D | Naitza, Silvia | Orrù, Marco | Palmer, Colin N A | Pouta, Anneli | Randall, Joshua | Rathmann, Wolfgang | Saramies, Jouko | Scheet, Paul | Scott, Laura J | Scuteri, Angelo | Sharp, Stephen | Sijbrands, Eric | Smit, Jan H | Song, Kijoung | Steinthorsdottir, Valgerdur | Stringham, Heather M | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Uitterlinden, André G | Voight, Benjamin F | Waterworth, Dawn | Wichmann, H-Erich | Willemsen, Gonneke | Witteman, Jacqueline C M | Yuan, Xin | Zhao, Jing Hua | Zeggini, Eleftheria | Schlessinger, David | Sandhu, Manjinder | Boomsma, Dorret I | Uda, Manuela | Spector, Tim D | Penninx, Brenda WJH | Altshuler, David | Vollenweider, Peter | Jarvelin, Marjo Riitta | Lakatta, Edward | Waeber, Gerard | Fox, Caroline S | Peltonen, Leena | Groop, Leif C | Mooser, Vincent | Cupples, L Adrienne | Thorsteinsdottir, Unnur | Boehnke, Michael | Barroso, Inês | Van Duijn, Cornelia | Dupuis, Josée | Watanabe, Richard M | Stefansson, Kari | McCarthy, Mark I | Wareham, Nicholas J | Meigs, James B | Abecasis, Gonçalo R
Nature genetics  2008;41(1):77-81.
To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 = × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci.
PMCID: PMC2682768  PMID: 19060907
13.  Copy number variation of the APC gene is associated with regulation of bone mineral density☆ 
Bone  2012;51(5):939-943.
Genetic studies of osteoporosis have commonly examined SNPs in candidate genes or whole genome analyses, but insertions and deletions of DNA, collectively called copy number variations (CNVs), also comprise a large amount of the genetic variability between individuals. Previously, SNPs in the APC gene have been strongly associated with femoral neck and lumbar spine volumetric bone mineral density in older men. In addition, familial adenomatous polyposis patients carrying heterozygous mutations in the APC gene have been shown to have significantly higher mean bone mineral density than age- and sex-matched controls suggesting the importance of this gene in regulating bone mineral density. We examined CNV within the APC gene region to test for association with bone mineral density.
DNA was extracted from venous blood, genotyped using the Human Hap610 arrays and CNV determined from the fluorescence intensity data in 2070 Caucasian men and women aged 47.0 ± 13.0 (mean ± SD) years, to assess the effects of the CNV on bone mineral density at the forearm, spine and total hip sites.
Data for covariate adjusted bone mineral density from subjects grouped by APC CNV genotype showed significant difference (P = 0.02–0.002). Subjects with a single copy loss of APC had a 7.95%, 13.10% and 13.36% increase in bone mineral density at the forearm, spine and total hip sites respectively, compared to subjects with two copies of the APC gene.
These data support previous findings of APC regulating bone mineral density and demonstrate that a novel CNV of the APC gene is significantly associated with bone mineral density in Caucasian men and women.
► Previously, SNPs in APC gene have been associated with volumetric BMD in older men. ► We examined CNV in the APC gene and found significant association with BMD in the TwinsUK cohort. ► The maximum difference between subjects with APC CNV and wild type was 13.4% at the total hip site. ► APC plays an important role in bone regulation via the Wnt signaling pathway.
PMCID: PMC3918860  PMID: 22884971
Bone mineral density; Osteoporosis; Copy number variation; APC; Association
14.  The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits 
PLoS Genetics  2012;8(8):e1002793.
Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the “Metabochip,” a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
Author Summary
Recent genetic studies have identified hundreds of regions of the human genome that contribute to risk for type 2 diabetes, coronary artery disease and myocardial infarction, and to related quantitative traits such as body mass index, glucose and insulin levels, blood lipid levels, and blood pressure. These results motivate two central questions: (1) can further genetic investigation identify additional associated regions?; and (2) can more detailed genetic investigation help us identify the causal variants (or variants more strongly correlated with the causal variants) in the regions identified so far? Addressing these questions requires assaying many genetic variants in DNA samples from thousands of individuals, which is expensive and timeconsuming when done a few SNPs at a time. To facilitate these investigations, we designed the “Metabochip,” a custom genotyping array that assays variation in nearly 200,000 sites in the human genome. Here we describe the Metabochip, evaluate its performance in assaying human genetic variation, and describe solutions to methodological challenges commonly encountered in its analysis.
PMCID: PMC3410907  PMID: 22876189
16.  Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways 
Diabetes  2010;59(12):3229-3239.
Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels.
We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.
Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c.
GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c.
PMCID: PMC2992787  PMID: 20858683
17.  Identification of an imprinted master trans-regulator at the KLF14 locus related to multiple metabolic phenotypes 
Nature genetics  2011;43(6):561-564.
Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whilst cis-regulatory patterns of gene expression have been extensively explored, the identification of trans-regulatory effects in humans has attracted less attention. We demonstrate that the Type 2 diabetes and HDL-cholesterol associated cis-acting eQTL of the maternally-expressed transcription factor KLF14 acts as a master trans-regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly-correlated with concurrently-measured metabolic traits, and a subset of the trans-genes harbor variants directly-associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk, providing a potential model for other complex traits.
PMCID: PMC3192952  PMID: 21572415
18.  A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol 
Surakka, Ida | Isaacs, Aaron | Karssen, Lennart C. | Laurila, Pirkka-Pekka P. | Middelberg, Rita P. S. | Tikkanen, Emmi | Ried, Janina S. | Lamina, Claudia | Mangino, Massimo | Igl, Wilmar | Hottenga, Jouke-Jan | Lagou, Vasiliki | van der Harst, Pim | Mateo Leach, Irene | Esko, Tõnu | Kutalik, Zoltán | Wainwright, Nicholas W. | Struchalin, Maksim V. | Sarin, Antti-Pekka | Kangas, Antti J. | Viikari, Jorma S. | Perola, Markus | Rantanen, Taina | Petersen, Ann-Kristin | Soininen, Pasi | Johansson, Åsa | Soranzo, Nicole | Heath, Andrew C. | Papamarkou, Theodore | Prokopenko, Inga | Tönjes, Anke | Kronenberg, Florian | Döring, Angela | Rivadeneira, Fernando | Montgomery, Grant W. | Whitfield, John B. | Kähönen, Mika | Lehtimäki, Terho | Freimer, Nelson B. | Willemsen, Gonneke | de Geus, Eco J. C. | Palotie, Aarno | Sandhu, Manj S. | Waterworth, Dawn M. | Metspalu, Andres | Stumvoll, Michael | Uitterlinden, André G. | Jula, Antti | Navis, Gerjan | Wijmenga, Cisca | Wolffenbuttel, Bruce H. R. | Taskinen, Marja-Riitta | Ala-Korpela, Mika | Kaprio, Jaakko | Kyvik, Kirsten O. | Boomsma, Dorret I. | Pedersen, Nancy L. | Gyllensten, Ulf | Wilson, James F. | Rudan, Igor | Campbell, Harry | Pramstaller, Peter P. | Spector, Tim D. | Witteman, Jacqueline C. M. | Eriksson, Johan G. | Salomaa, Veikko | Oostra, Ben A. | Raitakari, Olli T. | Wichmann, H.-Erich | Gieger, Christian | Järvelin, Marjo-Riitta | Martin, Nicholas G. | Hofman, Albert | McCarthy, Mark I. | Peltonen, Leena | van Duijn, Cornelia M. | Aulchenko, Yurii S. | Ripatti, Samuli | Gibson, Greg
PLoS Genetics  2011;7(10):e1002333.
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Author Summary
Circulating serum lipids contribute greatly to the global health by affecting the risk for cardiovascular diseases. Serum lipid levels are partly inherited, and already 95 loci affecting high- and low-density lipoprotein cholesterol, total cholesterol, and triglycerides have been found. Serum lipids are also known to be affected by multiple epidemiological risk factors like body composition, lifestyle, and sex. It has been hypothesized that there are loci modifying the effects between risk factors and serum lipids, but to date only candidate gene studies for interactions have been reported. We conducted a genome-wide screen with meta-analysis approach to identify loci having interactions with epidemiological risk factors on serum lipids with over 30,000 population-based samples. When combining results from our initial datasets and 8 additional replication cohorts (maximum N = 17,102), we found a genome-wide significant locus in chromosome 4p15 with a joint P-value of 4.79×10−9 modifying the effect of waist-to-hip ratio on total cholesterol. In the area surrounding this genetic variant, there were two genes having association between the genotypes and the gene expression in adipose tissue, and we also found enrichment of association in genes belonging to lipid metabolism related functions.
PMCID: PMC3197672  PMID: 22028671
19.  Genetic Determinants of Variability in Glycated Hemoglobin (HbA1c) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care 
Current Diabetes Reports  2011;11(6):562-569.
Glycated hemoglobin A1c (HbA1c) indicates the percentage of total hemoglobin that is bound by glucose, produced from the nonenzymatic chemical modification by glucose of hemoglobin molecules carried in erythrocytes. HbA1c represents a surrogate marker of average blood glucose concentration over the previous 8 to 12 weeks, or the average lifespan of the erythrocyte, and thus represents a more stable indicator of glycemic status compared with fasting glucose. HbA1c levels are genetically determined, with heritability of 47% to 59%. Over the past few years, inroads into understanding genetic predisposition by glycemic and nonglycemic factors have been achieved through genome-wide analyses. Here I review current research aimed at discovering genetic determinants of HbA1c levels, discussing insights into biologic factors influencing variability in the general and diabetic population, and across different ethnicities. Furthermore, I discuss briefly the relevance of findings for diabetes monitoring and diagnosis.
PMCID: PMC3207128  PMID: 21975967
Glycated hemoglobin; HbA1c; Genome-wide association study; Single nucleotide polymorphism; Genetic; Diabetes
21.  The Use of Genome-Wide eQTL Associations in Lymphoblastoid Cell Lines to Identify Novel Genetic Pathways Involved in Complex Traits 
PLoS ONE  2011;6(7):e22070.
The integrated analysis of genotypic and expression data for association with complex traits could identify novel genetic pathways involved in complex traits. We profiled 19,573 expression probes in Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from 299 twins and correlated these with 44 quantitative traits (QTs). For 939 expressed probes correlating with more than one QT, we investigated the presence of eQTL associations in three datasets of 57 CEU HapMap founders and 86 unrelated twins. Genome-wide association analysis of these probes with 2.2 m SNPs revealed 131 potential eQTLs (1,989 eQTL SNPs) overlapping between the HapMap datasets, five of which were in cis (58 eQTL SNPs). We then tested 535 SNPs tagging the eQTL SNPs, for association with the relevant QT in 2,905 twins. We identified nine potential SNP-QT associations (P<0.01) but none significantly replicated in five large consortia of 1,097–16,129 subjects. We also failed to replicate previous reported eQTL associations with body mass index, plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides levels derived from lymphocytes, adipose and liver tissue. Our results and additional power calculations suggest that proponents may have been overoptimistic in the power of LCLs in eQTL approaches to elucidate regulatory genetic effects on complex traits using the small datasets generated to date. Nevertheless, larger tissue-specific expression data sets relevant to specific traits are becoming available, and should enable the adoption of similar integrated analyses in the near future.
PMCID: PMC3137612  PMID: 21789213
22.  Maps of Open Chromatin Guide the Functional Follow-Up of Genome-Wide Association Signals: Application to Hematological Traits 
PLoS Genetics  2011;7(6):e1002139.
Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein–protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype.
Author Summary
Genome-wide scans have revealed multiple genetic regions underlying complex traits. However, the transition from an initial association signal to identifying the functional DNA change(s) has proved challenging. Many of the DNA changes discovered are located outside protein-coding regions and may exert their effects through gene regulation. We screened genetic regions associated with hematological traits in erythroblasts (red blood cells) and megakaryocytes (platelet-producing cells) and mapped sites of open chromatin, which harbor active gene regulatory elements. We investigated a DNA sequence change located within a site of open chromatin at chromosome 7 in megakaryocytes, but not erythroblasts, known to be associated with platelet volume. We showed that this DNA change is functional due to alteration of the binding site of a transcription factor, which regulates the expression of a gene that affects platelet characteristics. Mice lacking this gene revealed significant differences in expression of several important platelet genes compared to wild-type mice. The approach described here can be applied in different cell types to functionally follow-up association signals with many other biological traits by identification of the causative base change and how it affects gene function, thus paving the way to clinical benefit.
PMCID: PMC3128100  PMID: 21738486
23.  A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium 
Soranzo, Nicole | Spector, Tim D | Mangino, Massimo | Kühnel, Brigitte | Rendon, Augusto | Teumer, Alexander | Willenborg, Christina | Wright, Benjamin | Chen, Li | Li, Mingyao | Salo, Perttu | Voight, Benjamin F | Burns, Philippa | Laskowski, Roman A | Xue, Yali | Menzel, Stephan | Altshuler, David | Bradley, John R | Bumpstead, Suzannah | Burnett, Mary-Susan | Devaney, Joseph | Döring, Angela | Elosua, Roberto | Epstein, Stephen | Erber, Wendy | Falchi, Mario | Garner, Stephen F | Ghori, Mohammed J R | Goodall, Alison H | Gwilliam, Rhian | Hakonarson, Hakon H | Hall, Alistair S | Hammond, Naomi | Hengstenberg, Christian | Illig, Thomas | König, Inke R | Knouff, Christopher W | McPherson, Ruth | Melander, Olle | Mooser, Vincent | Nauck, Matthias | Nieminen, Markku S | O’Donnell, Christopher J | Peltonen, Leena | Potter, Simon C | Prokisch, Holger | Rader, Daniel J | Rice, Catherine M | Roberts, Robert | Salomaa, Veikko | Sambrook, Jennifer | Schreiber, Stefan | Schunkert, Heribert | Schwartz, Stephen M | Serbanovic-Canic, Jovana | Sinisalo, Juha | Siscovick, David S. | Stark, Klaus | Surakka, Ida | Stephens, Jonathan | Thompson, John R | Völker, Uwe | Völzke, Henry | Watkins, Nicholas A | Wells, George A | Wichmann, H-Erich | Van Heel, David A | Tyler-Smith, Chris | Thein, Swee Lay | Kathiresan, Sekar | Perola, Markus | Reilly, Muredach P | Stewart, Alexandre F R | Erdmann, Jeanette | Samani, Nilesh J | Meisinger, Christa | Greinacher, Andreas | Deloukas, Panos | Ouwehand, Willem H | Gieger, Christian
Nature genetics  2009;41(11):1182-1190.
The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
PMCID: PMC3108459  PMID: 19820697
24.  A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample 
PLoS ONE  2011;6(5):e19382.
Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).
To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.
We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.
The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers.
Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.
PMCID: PMC3098839  PMID: 21625484
25.  Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior 
Thorgeirsson, Thorgeir E. | Gudbjartsson, Daniel F. | Surakka, Ida | Vink, Jacqueline M. | Amin, Najaf | Geller, Frank | Sulem, Patrick | Rafnar, Thorunn | Esko, Tõnu | Walter, Stefan | Gieger, Christian | Rawal, Rajesh | Mangino, Massimo | Prokopenko, Inga | Mägi, Reedik | Keskitalo, Kaisu | Gudjonsdottir, Iris H. | Gretarsdottir, Solveig | Stefansson, Hreinn | Thompson, John R. | Aulchenko, Yurii S. | Nelis, Mari | Aben, Katja K. | den Heijer, Martin | Dirksen, Asger | Ashraf, Haseem | Soranzo, Nicole | Valdes, Ana M | Steves, Claire | Uitterlinden, André G | Hofman, Albert | Tönjes, Anke | Kovacs, Peter | Hottenga, Jouke Jan | Willemsen, Gonneke | Vogelzangs, Nicole | Döring, Angela | Dahmen, Norbert | Nitz, Barbara | Pergadia, Michele L. | Saez, Berta | De Diego, Veronica | Lezcano, Victoria | Garcia-Prats, Maria D. | Ripatti, Samuli | Perola, Markus | Kettunen, Johannes | Hartikainen, Anna-Liisa | Pouta, Anneli | Laitinen, Jaana | Isohanni, Matti | Huei-Yi, Shen | Allen, Maxine | Krestyaninova, Maria | Hall, Alistair S | Jones, Gregory T. | van Rij, Andre M. | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Jonsson, Steinn | Matthiasson, Stefan E. | Oskarsson, Hogni | Tyrfingsson, Thorarinn | Kiemeney, Lambertus A. | Mayordomo, Jose I. | Lindholt, Jes S | Pedersen, Jesper Holst | Franklin, Wilbur A. | Wolf, Holly | Montgomery, Grant W. | Heath, Andrew C. | Martin, Nicholas G. | Madden, Pamela A.F. | Giegling, Ina | Rujescu, Dan | Järvelin, Marjo-Riitta | Salomaa, Veikko | Stumvoll, Michael | Spector, Tim D | Wichmann, H-Erich | Metspalu, Andres | Samani, Nilesh J. | Penninx, Brenda W. | Oostra, Ben A. | Boomsma, Dorret I. | Tiemeier, Henning | van Duijn, Cornelia M. | Kaprio, Jaakko | Gulcher, Jeffrey R. | McCarthy, Mark I. | Peltonen, Leena | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(5):448-453.
Smoking is a risk factor for most of the diseases leading in mortality1. We conducted genome-wide association (GWA) meta-analyses of smoking data within the ENGAGE consortium to search for common alleles associating with the number of cigarettes smoked per day (CPD) in smokers (N=31,266) and smoking initiation (N=46,481). We tested selected SNPs in a second stage (N=45,691 smokers), and assessed some in a third sample (N=9,040). Variants in three genomic regions associated with CPD (P< 5·10−8), including previously identified SNPs at 15q25 represented by rs1051730-A (0.80 CPD,P=2.4·10−69), and SNPs at 19q13 and 8p11, represented by rs4105144-C (0.39 CPD, P=2.2·10−12) and rs6474412-T (0.29 CPD,P= 1.4·10−8), respectively. Among the genes at the two novel loci, are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6), and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6) highlighted in previous studies of nicotine dependence2-3. Nominal associations with lung cancer were observed at both 8p11 (rs6474412-T,OR=1.09,P=0.04) and 19q13 (rs4105144-C,OR=1.12,P=0.0006).
PMCID: PMC3080600  PMID: 20418888

Results 1-25 (59)