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author:("suraksha, Ida")
1.  Genetic variants influencing circulating lipid levels and risk of coronary artery disease 
Objectives
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9).
Conclusions
We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
doi:10.1161/ATVBAHA.109.201020
PMCID: PMC3891568  PMID: 20864672
lipids; lipoproteins; genetics; epidemiology
2.  Partial Sleep Restriction Activates Immune Response-Related Gene Expression Pathways: Experimental and Epidemiological Studies in Humans 
PLoS ONE  2013;8(10):e77184.
Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling (P<0.005). Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.
doi:10.1371/journal.pone.0077184
PMCID: PMC3806729  PMID: 24194869
3.  Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits 
Diabetes  2012;61(8):2176-2186.
Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.
doi:10.2337/db11-1515
PMCID: PMC3402303  PMID: 22698912
4.  Association of LIN28B with Adult Adiposity-Related Traits in Females 
PLoS ONE  2012;7(11):e48785.
Context
Pubertal timing is under strong genetic control and its early onset associates with several adverse health outcomes in adulthood, including obesity, type 2 diabetes and cardiovascular disease. Recent data indicate strong association between pubertal timing and genetic variants near LIN28B, but it is currently unknown whether the gene contributes to the association between puberty and adult disease.
Objective
To elucidate the putative genetic link between early puberty and adult disease risk, we examined the association of two genetic variants near LIN28B with adult body size and metabolic profiles in randomly ascertained adult Finnish males and females.
Methods
Two single nucleotide polymorphisms (SNPs), rs7759938, the lead SNP previously associated with pubertal timing and height, and rs314279, previously also associated with menarcheal age but only partially correlated with rs7759938 (r2 = 0.30), were genotyped in 26,636 study subjects participating in the Finnish population survey FINRISK. Marker associations with adult height, weight, body mass index (BMI), hip and waist circumference, blood glucose, serum insulin and lipid/lipoprotein levels were determined by linear regression analyses.
Results
Both rs7759938 and rs314279 associated with adult height in both sexes (p = 2×10−6 and p = 0.001). Furthermore, rs314279 associated with increased weight in females (p = 0.001). Conditioned analyses including both SNPs in the regression model verified that rs314279 independently associates with adult female weight, BMI and hip circumference (p<0.005). Neither SNP associated with glucose, lipid, or lipoprotein levels.
Conclusion
Genetic variants near the puberty-associated gene LIN28B associate with adult weight and body shape in females, suggesting that the gene may tag molecular pathways influencing adult adiposity-related traits.
doi:10.1371/journal.pone.0048785
PMCID: PMC3496729  PMID: 23152804
5.  Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution but No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits 
Background
Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS.
Methods and Results
A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status.
Conclusions
Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance.
doi:10.1161/CIRCGENETICS.111.961482
PMCID: PMC3378651  PMID: 22399527
metabolic syndrome; risk factors; genome-wide association study; meta-analysis; lipids
6.  Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects 
Background
To get insight into molecular mechanisms underlying insulin resistance, we compared acute in vivo effects of insulin on adipose tissue transcriptional profiles between obese insulin-resistant and lean insulin-sensitive women.
Methods
Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 hours of intravenously maintained euglycemic hyperinsulinemia from 9 insulin-resistant and 11 insulin-sensitive females. Gene expression was measured using Affymetrix HG U133 Plus 2 microarrays and qRT-PCR. Microarray data and pathway analyses were performed with Chipster v1.4.2 and by using in-house developed nonparametric pathway analysis software.
Results
The most prominent difference in gene expression of the insulin-resistant group during hyperinsulinemia was reduced transcription of nuclear genes involved in mitochondrial respiration (mitochondrial respiratory chain, GO:0001934). Inflammatory pathways with complement components (inflammatory response, GO:0006954) and cytokines (chemotaxis, GO:0042330) were strongly up-regulated in insulin-resistant as compared to insulin-sensitive subjects both before and during hyperinsulinemia. Furthermore, differences were observed in genes contributing to fatty acid, cholesterol and triglyceride metabolism (FATP2, ELOVL6, PNPLA3, SREBF1) and in genes involved in regulating lipolysis (ANGPTL4) between the insulin-resistant and -sensitive subjects especially during hyperinsulinemia.
Conclusions
The major finding of this study was lower expression of mitochondrial respiratory pathway and defective induction of lipid metabolism pathways by insulin in insulin-resistant subjects. Moreover, the study reveals several novel genes whose aberrant regulation is associated with the obese insulin-resistant phenotype.
doi:10.1186/1755-8794-5-9
PMCID: PMC3384471  PMID: 22471940
7.  Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function 
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
doi:10.1164/rccm.201102-0192OC
PMCID: PMC3398416  PMID: 21965014
FEV1; FVC; genome-wide association study; modeling risk
8.  NordicDB: a Nordic pool and portal for genome-wide control data 
European Journal of Human Genetics  2010;18(12):1322-1326.
A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from ∼5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW–SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries.
doi:10.1038/ejhg.2010.112
PMCID: PMC3002853  PMID: 20664631
common controls; genome-wide data; Nordic Control Database; population stratification
9.  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.
doi:10.1371/journal.pgen.1002333
PMCID: PMC3197672  PMID: 22028671
10.  Meta-analysis of genome-wide association studies in >80,000 subjects identifies multiple loci for C-reactive protein levels 
Dehghan, Abbas | Dupuis, Josée | Barbalic, Maja | Bis, Joshua C | Eiriksdottir, Gudny | Lu, Chen | Pellikka, Niina | Wallaschofski, Henri | Kettunen, Johannes | Henneman, Peter | Baumert, Jens | Strachan, David P | Fuchsberger, Christian | Vitart, Veronique | Wilson, James F | Paré, Guillaume | Naitza, Silvia | Rudock, Megan E | Surakka, Ida | de Geus, Eco JC | Alizadeh, Behrooz Z | Guralnik, Jack | Shuldiner, Alan | Tanaka, Toshiko | Zee, Robert YL | Schnabel, Renate B | Nambi, Vijay | Kavousi, Maryam | Ripatti, Samuli | Nauck, Matthias | Smith, Nicholas L | Smith, Albert V | Sundvall, Jouko | Scheet, Paul | Liu, Yongmei | Ruokonen, Aimo | Rose, Lynda M | Larson, Martin G | Hoogeveen, Ron C | Freimer, Nelson B | Teumer, Alexander | Tracy, Russell P | Launer, Lenore J | Buring, Julie E | Yamamoto, Jennifer F | Folsom, Aaron R | Sijbrands, Eric JG | Pankow, James | Elliott, Paul | Keaney, John F | Sun, Wei | Sarin, Antti-Pekka | Fontes, João D | Badola, Sunita | Astor, Brad C | Hofman, Albert | Pouta, Anneli | Werdan, Karl | Greiser, Karin H | Kuss, Oliver | Meyer zu Schwabedissen, Henriette E | Thiery, Joachim | Jamshidi, Yalda | Nolte, Ilja M | Soranzo, Nicole | Spector, Timothy D | Völzke, Henry | Parker, Alexander N | Aspelund, Thor | Bates, David | Young, Lauren | Tsui, Kim | Siscovick, David S | Guo, Xiuqing | Rotter, Jerome I | Uda, Manuela | Schlessinger, David | Rudan, Igor | Hicks, Andrew A | Penninx, Brenda W | Thorand, Barbara | Gieger, Christian | Coresh, Joe | Willemsen, Gonneke | Harris, Tamara B | Uitterlinden, Andre G | Järvelin, Marjo-Riitta | Rice, Kenneth | Radke, Dörte | Salomaa, Veikko | van Dijk, Ko Willems | Boerwinkle, Eric | Vasan, Ramachandran S | Ferrucci, Luigi | Gibson, Quince D | Bandinelli, Stefania | Snieder, Harold | Boomsma, Dorret I | Xiao, Xiangjun | Campbell, Harry | Hayward, Caroline | Pramstaller, Peter P | van Duijn, Cornelia M | Peltonen, Leena | Psaty, Bruce M | Gudnason, Vilmundur | Ridker, Paul M | Homuth, Georg | Koenig, Wolfgang | Ballantyne, Christie M | Witteman, Jacqueline CM | Benjamin, Emelia J | Perola, Markus | Chasman, Daniel I
Circulation  2011;123(7):731-738.
Background
C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We aimed to identify genetic variants that are associated with CRP levels.
Methods and Results
We performed a genome wide association (GWA) analysis of CRP in 66,185 participants from 15 population-based studies. We sought replication for the genome wide significant and suggestive loci in a replication panel comprising 16,540 individuals from ten independent studies. We found 18 genome-wide significant loci and we provided evidence of replication for eight of them. Our results confirm seven previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2), immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1), or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found significant interaction of body mass index (BMI) with LEPR (p<2.9×10−6). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximately 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.
Conclusion
We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
doi:10.1161/CIRCULATIONAHA.110.948570
PMCID: PMC3147232  PMID: 21300955
genome-wide association; C-reactive protein; inflammation; epidemiology; coronary heart disease
11.  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.
doi:10.1371/journal.pone.0022070
PMCID: PMC3137612  PMID: 21789213
12.  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).
doi:10.1038/ng.573
PMCID: PMC3080600  PMID: 20418888
13.  Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15 
Human Molecular Genetics  2009;18(20):4007-4012.
A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates nicotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30–75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R2 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
doi:10.1093/hmg/ddp322
PMCID: PMC2748889  PMID: 19628476
14.  Genome-wide association study identifies five loci associated with lung function 
Repapi, Emmanouela | Sayers, Ian | Wain, Louise V | Burton, Paul R | Johnson, Toby | Obeidat, Ma’en | Zhao, Jing Hua | Ramasamy, Adaikalavan | Zhai, Guangju | Vitart, Veronique | Huffman, Jennifer E | Igl, Wilmar | Albrecht, Eva | Deloukas, Panos | Henderson, John | Granell, Raquel | McArdle, Wendy L | Rudnicka, Alicja R | Barroso, Inês | Loos, Ruth J F | Wareham, Nicholas J | Mustelin, Linda | Rantanen, Taina | Surakka, Ida | Imboden, Medea | Wichmann, H Erich | Grkovic, Ivica | Jankovic, Stipan | Zgaga, Lina | Hartikainen, Anna-Liisa | Peltonen, Leena | Gyllensten, Ulf | Johansson, Åsa | Zaboli, Ghazal | Campbell, Harry | Wild, Sarah H | Wilson, James F | Gläser, Sven | Homuth, Georg | Völzke, Henry | Mangino, Massimo | Soranzo, Nicole | Spector, Tim D | Polašek, Ozren | Rudan, Igor | Wright, Alan F | Heliövaara, Markku | Ripatti, Samuli | Pouta, Anneli | Naluai, Åsa Torinsson | Olin, Anna-Carin | Torén, Kjell | Cooper, Matthew N | James, Alan L | Palmer, Lyle J | Hingorani, Aroon D | Wannamethee, S Goya | Whincup, Peter H | Smith, George Davey | Ebrahim, Shah | McKeever, Tricia M | Pavord, Ian D | MacLeod, Andrew K | Morris, Andrew D | Porteous, David J | Cooper, Cyrus | Dennison, Elaine | Shaheen, Seif | Karrasch, Stefan | Schnabel, Eva | Schulz, Holger | Grallert, Harald | Bouatia-Naji, Nabila | Delplanque, Jérôme | Froguel, Philippe | Blakey, John D | Britton, John R | Morris, Richard W | Holloway, John W | Lawlor, Debbie A | Hui, Jennie | Nyberg, Fredrik | Jarvelin, Marjo-Riitta | Jackson, Cathy | Kähönen, Mika | Kaprio, Jaakko | Probst-Hensch, Nicole M | Koch, Beate | Hayward, Caroline | Evans, David M | Elliott, Paul | Strachan, David P | Hall, Ian P | Tobin, Martin D
Nature genetics  2009;42(1):36-44.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
doi:10.1038/ng.501
PMCID: PMC2862965  PMID: 20010834
15.  Use of Genome-Wide Expression Data to Mine the “Gray Zone” of GWA Studies Leads to Novel Candidate Obesity Genes 
PLoS Genetics  2010;6(6):e1000976.
To get beyond the “low-hanging fruits” so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24–28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N = 77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N = 21,000) revealed a significant deviation of P-values from the expected (P = 4×10−4). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of ∼2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity.
Author Summary
Obesity has a strong genetic component and an estimated 45%–85% of the variation in adult relative weight is genetically determined. Many genes have recently been identified in genome-wide association studies. The individual effects of the identified genes, however, have been very modest, and their identification required very large sample sizes. New approaches are therefore needed to uncover further genetic variants that contribute to the development of obesity and related conditions. Much can be learned from studying the expression of genes in adipose tissue of obese and non-obese subjects, but it is very difficult to distinguish which genes' expression differences represent reactions to obesity from those related to causal processes. We studied monozygotic twin pairs discordant for obesity and contrasted the gene expression profiles of obese and lean co-twins (controlling for genetic variation) to those from unrelated individuals to try to discern the cause-and-effect relationships of the identified changes in gene expression in fat. Testing the identified genes in 21,000 individuals identified numerous new genes with possible roles in the development of obesity. Among the top findings was a gene involved in blood coagulation (Factor XIIIA1), possibly linking obesity with known complications including deep vein thrombosis, heart attack, and stroke.
doi:10.1371/journal.pgen.1000976
PMCID: PMC2880558  PMID: 20532202
16.  Childhood Adversities Are Associated with Shorter Telomere Length at Adult Age both in Individuals with an Anxiety Disorder and Controls 
PLoS ONE  2010;5(5):e10826.
Accelerated leukocyte telomere shortening has been previously associated to self-perceived stress and psychiatric disorders, including schizophrenia and mood disorders. We set out to investigate whether telomere length is affected in patients with anxiety disorders in which stress is a known risk factor. We also studied the effects of childhood and recent psychological distress on telomere length. We utilized samples from the nationally representative population-based Health 2000 Survey that was carried out between 2000–2001 in Finland to assess major public health problems and their determinants. We measured the relative telomere length of the peripheral blood cells by quantitative real-time PCR from 321 individuals with DSM-IV anxiety disorder or subthreshold diagnosis and 653 matched controls aged 30–87 years, who all had undergone the Composite International Diagnostic Interview. While telomere length did not differ significantly between cases and controls in the entire cohort, the older half of the anxiety disorder patients (48–87 years) exhibited significantly shorter telomeres than healthy controls of the same age (P = 0.013). Interestingly, shorter telomere length was also associated with a greater number of reported childhood adverse life events, among both the anxiety disorder cases and controls (P = 0.005). Childhood chronic or serious illness was the most significantly associated single event affecting telomere length at the adult age (P = 0.004). Self-reported current psychological distress did not affect telomere length. Our results suggest that childhood stress might lead to accelerated telomere shortening seen at the adult age. This finding has potentially important implications supporting the view that childhood adversities might have a considerable impact on well being later in life.
doi:10.1371/journal.pone.0010826
PMCID: PMC2876034  PMID: 20520834
17.  European lactase persistence genotype shows evidence of association with increase in body mass index 
Human Molecular Genetics  2009;19(6):1129-1136.
The global prevalence of obesity has increased significantly in recent decades, mainly due to excess calorie intake and increasingly sedentary lifestyle. Here, we test the association between obesity measured by body mass index (BMI) and one of the best-known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments. We genetically defined lactase persistence (LP) in 31 720 individuals from eight European population-based studies and one family study by genotyping or imputing the European LP variant (rs4988235). We performed a meta-analysis by pooling the β-coefficient estimates of the relationship between rs4988235 and BMI from the nine studies and found that the carriers of the allele responsible for LP among Europeans showed higher BMI (P = 7.9 × 10−5). Since this locus has been shown to be prone to population stratification, we paid special attention to reveal any population substructure which might be responsible for the association signal. The best evidence of exclusion of stratification came from the Dutch family sample which is robust for stratification. In this study, we highlight issues in model selection in the genome-wide association studies and problems in imputation of these special genomic regions.
doi:10.1093/hmg/ddp561
PMCID: PMC2830824  PMID: 20015952
18.  OSBPL10, a novel candidate gene for high triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid metabolism 
Analysis of variants in three genes encoding oxysterol-binding protein (OSBP) homologues (OSBPL2, OSBPL9, OSBPL10) in Finnish families with familial low high-density lipoprotein (HDL) levels (N = 426) or familial combined hyperlipidemia (N = 684) revealed suggestive linkage of OSBPL10 single-nucleotide polymorphisms (SNPs) with extreme end high triglyceride (TG; >90th percentile) trait. Prompted by this initial finding, we carried out association analysis in a metabolic syndrome subcohort (Genmets) of Health2000 examination survey (N = 2,138), revealing association of multiple OSBPL10 SNPs with high serum TG levels (>95th percentile). To investigate whether OSBPL10 could be the gene underlying the observed linkage and association, we carried out functional experiments in the human hepatoma cell line Huh7. Silencing of OSBPL10 increased the incorporation of [3H]acetate into cholesterol and both [3H]acetate and [3H]oleate into triglycerides and enhanced the accumulation of secreted apolipoprotein B100 in growth medium, suggesting that the encoded protein ORP10 suppresses hepatic lipogenesis and very-low-density lipoprotein production. ORP10 was shown to associate dynamically with microtubules, consistent with its involvement in intracellular transport or organelle positioning. The data introduces OSBPL10 as a gene whose variation may contribute to high triglyceride levels in dyslipidemic Finnish subjects and provides evidence for ORP10 as a regulator of cellular lipid metabolism.
Electronic supplementary material
The online version of this article (doi:10.1007/s00109-009-0490-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00109-009-0490-z
PMCID: PMC2707950  PMID: 19554302
Cholesterol; High-density lipoprotein; Microtubule; Oxysterol-binding protein; Single-nucleotide polymorphism; Triglyceride

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