PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-20 (20)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
1.  Lung Cancer Risk Among Hairdressers: A Pooled Analysis of Case-Control Studies Conducted Between 1985 and 2010 
American Journal of Epidemiology  2013;178(9):1355-1365.
Increased lung cancer risks among hairdressers were observed in large registry-based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case-control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95% confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95% CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio = 2.66, 95% CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio = 2.20, 95% CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies.
doi:10.1093/aje/kwt119
PMCID: PMC3813309  PMID: 24068200
case-control studies; hair bleaching agents; hair color; lung neoplasms; occupational exposure
2.  Genome-wide meta-analysis identifies new susceptibility loci for migraine 
Anttila, Verneri | Winsvold, Bendik S. | Gormley, Padhraig | Kurth, Tobias | Bettella, Francesco | McMahon, George | Kallela, Mikko | Malik, Rainer | de Vries, Boukje | Terwindt, Gisela | Medland, Sarah E. | Todt, Unda | McArdle, Wendy L. | Quaye, Lydia | Koiranen, Markku | Ikram, M. Arfan | Lehtimäki, Terho | Stam, Anine H. | Ligthart, Lannie | Wedenoja, Juho | Dunham, Ian | Neale, Benjamin M. | Palta, Priit | Hamalainen, Eija | Schürks, Markus | Rose, Lynda M | Buring, Julie E. | Ridker, Paul M. | Steinberg, Stacy | Stefansson, Hreinn | Jakobsson, Finnbogi | Lawlor, Debbie A. | Evans, David M. | Ring, Susan M. | Färkkilä, Markus | Artto, Ville | Kaunisto, Mari A | Freilinger, Tobias | Schoenen, Jean | Frants, Rune R. | Pelzer, Nadine | Weller, Claudia M. | Zielman, Ronald | Heath, Andrew C. | Madden, Pamela A.F. | Montgomery, Grant W. | Martin, Nicholas G. | Borck, Guntram | Göbel, Hartmut | Heinze, Axel | Heinze-Kuhn, Katja | Williams, Frances M.K. | Hartikainen, Anna-Liisa | Pouta, Anneli | van den Ende, Joyce | Uitterlinden, Andre G. | Hofman, Albert | Amin, Najaf | Hottenga, Jouke-Jan | Vink, Jacqueline M. | Heikkilä, Kauko | Alexander, Michael | Muller-Myhsok, Bertram | Schreiber, Stefan | Meitinger, Thomas | Wichmann, Heinz Erich | Aromaa, Arpo | Eriksson, Johan G. | Traynor, Bryan | Trabzuni, Daniah | Rossin, Elizabeth | Lage, Kasper | Jacobs, Suzanne B.R. | Gibbs, J. Raphael | Birney, Ewan | Kaprio, Jaakko | Penninx, Brenda W. | Boomsma, Dorret I. | van Duijn, Cornelia | Raitakari, Olli | Jarvelin, Marjo-Riitta | Zwart, John-Anker | Cherkas, Lynn | Strachan, David P. | Kubisch, Christian | Ferrari, Michel D. | van den Maagdenberg, Arn M.J.M. | Dichgans, Martin | Wessman, Maija | Smith, George Davey | Stefansson, Kari | Daly, Mark J. | Nyholt, Dale R. | Chasman, Daniel | Palotie, Aarno
Nature genetics  2013;45(8):912-917.
doi:10.1038/ng.2676
PMCID: PMC4041123  PMID: 23793025
3.  PLA1A2 platelet polymorphism predicts mortality in prediabetic subjects of the population based KORA S4-Cohort 
Objective
The genetic polymorphism concerning the ß3-subunit of platelet integrin receptor glycoprotein IIIa is held responsible for enhanced binding of adhesive proteins resulting in increased thrombogenic potential. Whether it is associated with mortality, HbA1c or platelet volume is tested prospectively in an epidemiological cohort.
Research design and methods
Population-based Cooperative Health Research in the Region of Augsburg (KORA) S4-Survey (N = 4,028) was investigated for prognostic value of PLA1A2-polymorphism regarding all-cause mortality, correlation with HbA1c, and mean platelet volume. Multivariate analysis was performed to investigate association between genotype and key variables.
Results
Prevalence of thrombogenic allele variant PLA2 was 15.0%. Multivariate analysis revealed no association between PLA1A2 polymorphism and mortality in the KORA-cohort. HbA1c was a prognostic marker of mortality in non-diabetic persons resulting in J-shaped risk curve with dip at HbA1c = 5.5% (37 mmol/mol), confirming previous findings regarding aged KORA-S4 participants (55–75 years). PLA1A2 was significantly associated with elevated HbA1c levels in diabetic patients (N = 209) and reduced mean platelet volume in general population. In non-diabetic participants (N = 3,819), carriers of PLA2 allele variant presenting with HbA1c > 5.5% (37 mmol/mol) showed higher relative risk of mortality with increasing HbA1c.
Conclusion
PLA1A2 polymorphism is associated with mortality in participants with HbA1c ranging from 5.5% (37 mmol/mol) to 6.5% (48 mmol/mol). Maintenance of euglycemic control and antiplatelet therapy are therefore regarded as effective primary prevention in this group.
doi:10.1186/1475-2840-13-90
PMCID: PMC4022397  PMID: 24886443
Glycated hemoglobin; Platelet glycoprotein receptor polymorphism; Mean platelet volume; All-cause mortality; Glycemic management; Epidemiology
4.  Mitochondrial DNA Variants in Obesity 
PLoS ONE  2014;9(5):e94882.
Heritability estimates for body mass index (BMI) variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s) in the exclusively maternally inherited mitochondrial DNA (mtDNA) might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs) were available from genome-wide association study SNP arrays (Affymetrix 6.0). For discovery, we analyzed association in a case-control (CC) sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI≥30 kg/m2) and n = 2,373 normal weight and lean controls (BMI<25 kg/m2). SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger) in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002) located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039). These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048). Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their offspring could not be substantiated by the findings of the present study.
doi:10.1371/journal.pone.0094882
PMCID: PMC4008486  PMID: 24788344
5.  Evaluation of the Impact of Low Emission Zone and Heavy Traffic Ban in Munich (Germany) on the Reduction of PM10 in Ambient Air 
Concentrations of ambient fine particles (PM10: particles with an aerodynamic diameter ≤ 10 µm) are still exceeding current air quality standards in many European cities. In Munich (Germany), low emission zone and transit bans for heavy-duty vehicles were introduced in 2008 aiming at reduction of traffic emissions contribution to PM10. The effects of those measures on PM10 mass concentrations in Munich were investigated with a semiparametric regression model for modeling PM10 levels adjusted for time, background pollution, public holidays and wind direction. The reduction of PM10 concentration after the introduction of the measures was larger at a traffic monitoring site (13.0 %, 19.6 % in summer, and 6.8 % in winter) and smaller in urban background (4.5 %, 5.7 % in summer, and 3.2 % in winter). The effect was most pronounced on Fridays and on the weekends in summer.
doi:10.3390/ijerph110505094
PMCID: PMC4053866  PMID: 24828081
fine particles; PM10; low emission zone; truck ban; Munich
6.  Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies 
Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. Using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% CI 74.8-143.2) for SqCC, 111.3 (95% CI 69.8-177.5) for SCLC, and 21.9 (95% CI 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI 31.5-124.6), 108.6 (95% CI 50.7-232.8), and 16.8 (95% CI 9.2-30.6), respectively. Whereas ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.
doi:10.1002/ijc.27339
PMCID: PMC3296911  PMID: 22052329
cigarette smoking; lung cancer; relative risk characterization; tobacco smoke; stem cells
7.  Gene Set of Nuclear-Encoded Mitochondrial Regulators Is Enriched for Common Inherited Variation in Obesity 
PLoS ONE  2013;8(2):e55884.
There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50th and 95th percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50th percentile for the set of the 16 nuclear regulators of mitochondrial genes (pGSEA,50 = 0.0103). This finding was not confirmed in the trios (pGSEA,50 = 0.5991), but in KORA (pGSEA,50 = 0.0398). The meta-analysis again indicated a trend for enrichment (pMAGENTA,50 = 0.1052, pMAGENTA,75 = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes.
doi:10.1371/journal.pone.0055884
PMCID: PMC3568071  PMID: 23409076
8.  Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants 
BMC Medical Genomics  2012;5:65.
Background
The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.
Methods
We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro.
Results
We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ.
Conclusion
The rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.
doi:10.1186/1755-8794-5-65
PMCID: PMC3544595  PMID: 23270367
SH2B1; Obesity; BMI; rs7498665; Mutation screen
9.  A Genome-wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease 
Wild, Philipp S | Zeller, Tanja | Schillert, Arne | Szymczak, Silke | Sinning, Christoph R | Deiseroth, Arne | Schnabel, Renate B | Lubos, Edith | Keller, Till | Eleftheriadis, Medea S | Bickel, Christoph | Rupprecht, Hans J | Wilde, Sandra | Rossmann, Heidi | Diemert, Patrick | Cupples, L Adrienne | Perret, Claire | Erdmann, Jeanette | Stark, Klaus | Kleber, Marcus E | Epstein, Stephen E | Voight, Benjamin F | Kuulasmaa, Kari | Li, Mingyao | Schäfer, Arne S | Klopp, Norman | Braund, Peter S | Sager, Hendrik B | Demissie, Serkalem | Proust, Carole | König, Inke R | Wichmann, Heinz-Erich | Reinhard, Wibke | Hoffmann, Michael M | Virtamo, Jarmo | Burnett, Mary Susan | Siscovick, David | Wiklund, Per Gunnar | Qu, Liming | El Mokthari, Nour Eddine | Thompson, John R | Peters, Annette | Smith, Albert V | Yon, Emmanuelle | Baumert, Jens | Hengstenberg, Christian | März, Winfried | Amouyel, Philippe | Devaney, Joseph | Schwartz, Stephen M | Saarela, Olli | Mehta, Nehal N | Rubin, Diana | Silander, Kaisa | Hall, Alistair S | Ferrieres, Jean | Harris, Tamara B | Melander, Olle | Kee, Frank | Hakonarson, Hakon | Schrezenmeir, Juergen | Gudnason, Vilmundur | Elosua, Roberto | Arveiler, Dominique | Evans, Alun | Rader, Daniel J | Illig, Thomas | Schreiber, Stefan | Bis, Joshua C | Altshuler, David | Kavousi, Maryam | Witteman, Jaqueline CM | Uitterlinden, Andre G | Hofman, Albert | Folsom, Aaron R | Barbalic, Maja | Boerwinkle, Eric | Kathiresan, Sekar | Reilly, Muredach P | O'Donnell, Christopher J | Samani, Nilesh J | Schunkert, Heribert | Cambien, Francois | Lackner, Karl J | Tiret, Laurence | Salomaa, Veikko | Munzel, Thomas | Ziegler, Andreas | Blankenberg, Stefan
Background
eQTL analyses are important to improve the understanding of genetic association results. Here, we performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).
Methods and Results
In a genome-wide association analysis of 2,078 CAD cases and 2,953 controls, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10-3. Subsequent in silico and wet-lab replication stages and a final meta-analysis of 21,428 CAD cases and 38,361 controls revealed a novel association signal at chromosome 10q23.31 within the LIPA (Lysosomal Acid Lipase A) gene (P=3.7×10-8; OR 1.1; 95% CI: 1.07-1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1,494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10-96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10-3).
Conclusions
The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which itself was related to endothelial dysfunction, a precursor of CAD.
doi:10.1161/CIRCGENETICS.110.958728
PMCID: PMC3157552  PMID: 21606135
coronary artery disease; genome-wide association studies; gene expression; genetic variation; genomics; eQTL; eSNP; LIPA
10.  Genetic architecture of circulating lipid levels 
Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
doi:10.1038/ejhg.2011.21
PMCID: PMC3137496  PMID: 21448234
serum lipids; polygenic; genome-wide association; polygenic score; pathway analysis
11.  Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers 
PLoS Genetics  2011;7(8):e1002215.
Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10−4; Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10−10; Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
Author Summary
The combination of genomic and metabolic studies during the last years has provided astonishing results. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by sex. The investigation of 131 serum metabolite concentrations of >3,300 population-based samples (KORA F3/F4) revealed significant differences in the metabolite profile of males and females. Furthermore, a genome-wide picture of sex-specific genetic variations in human metabolism (>2,000 subjects from KORA F3/F4 cohorts) was investigated. Sex-specific genome-wide association studies (GWAS) showed differences in the effect of genetic variations on metabolites in men and women. SNPs in the CPS1 (carbamoyl-phosphate synthase 1) locus showed genome-wide significant differences in beta-estimates of sex-specific association analysis (significance level: 3.8×10−10) for glycine. As global metabolomic techniques are more and more refined to identify more compounds in single biological samples, the predictive power of this new technology will greatly increase. This suggests that metabolites, which may be used as predictive biomarkers to indicate the presence or severity of a disease, have to be used selectively depending on sex.
doi:10.1371/journal.pgen.1002215
PMCID: PMC3154959  PMID: 21852955
12.  Population-genetic comparison of the Sorbian isolate population in Germany with the German KORA population using genome-wide SNP arrays 
BMC Genetics  2011;12:67.
Background
The Sorbs are an ethnic minority in Germany with putative genetic isolation, making the population interesting for disease mapping. A sample of N = 977 Sorbs is currently analysed in several genome-wide meta-analyses. Since genetic differences between populations are a major confounding factor in genetic meta-analyses, we compare the Sorbs with the German outbred population of the KORA F3 study (N = 1644) and other publically available European HapMap populations by population genetic means. We also aim to separate effects of over-sampling of families in the Sorbs sample from effects of genetic isolation and compare the power of genetic association studies between the samples.
Results
The degree of relatedness was significantly higher in the Sorbs. Principal components analysis revealed a west to east clustering of KORA individuals born in Germany, KORA individuals born in Poland or Czech Republic, Half-Sorbs (less than four Sorbian grandparents) and Full-Sorbs. The Sorbs cluster is nearest to the cluster of KORA individuals born in Poland. The number of rare SNPs is significantly higher in the Sorbs sample. FST between KORA and Sorbs is an order of magnitude higher than between different regions in Germany. Compared to the other populations, Sorbs show a higher proportion of individuals with runs of homozygosity between 2.5 Mb and 5 Mb. Linkage disequilibrium (LD) at longer range is also slightly increased but this has no effect on the power of association studies.
Oversampling of families in the Sorbs sample causes detectable bias regarding higher FST values and higher LD but the effect is an order of magnitude smaller than the observed differences between KORA and Sorbs. Relatedness in the Sorbs also influenced the power of uncorrected association analyses.
Conclusions
Sorbs show signs of genetic isolation which cannot be explained by over-sampling of relatives, but the effects are moderate in size. The Slavonic origin of the Sorbs is still genetically detectable.
Regarding LD structure, a clear advantage for genome-wide association studies cannot be deduced. The significant amount of cryptic relatedness in the Sorbs sample results in inflated variances of Beta-estimators which should be considered in genetic association analyses.
doi:10.1186/1471-2156-12-67
PMCID: PMC3199861  PMID: 21798003
14.  Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies 
Brain  2009;133(1):23-32.
Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8–13.2; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 10−7). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8–13.2; P = 4.2 × 10−4) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3–74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
doi:10.1093/brain/awp262
PMCID: PMC2801323  PMID: 19843651
idiopathic generalized epilepsy; microdeletions; association; genetics
15.  CONAN: copy number variation analysis software for genome-wide association studies 
BMC Bioinformatics  2010;11:318.
Background
Genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) revolutionized our perception of the genetic regulation of complex traits and diseases. Copy number variations (CNVs) promise to shed additional light on the genetic basis of monogenic as well as complex diseases and phenotypes. Indeed, the number of detected associations between CNVs and certain phenotypes are constantly increasing. However, while several software packages support the determination of CNVs from SNP chip data, the downstream statistical inference of CNV-phenotype associations is still subject to complicated and inefficient in-house solutions, thus strongly limiting the performance of GWAS based on CNVs.
Results
CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data.
Conclusions
CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at.
doi:10.1186/1471-2105-11-318
PMCID: PMC2894823  PMID: 20546565
16.  An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population 
Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene–disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.
doi:10.1038/ejhg.2008.266
PMCID: PMC2986489  PMID: 19156175
population structure; matching; association; ancestry; microarray
17.  Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene 
BMC Cancer  2008;8:113.
The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis.
We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking.
Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7–1.5) and 1.0 (95% CI: 0.7–1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.
doi:10.1186/1471-2407-8-113
PMCID: PMC2377274  PMID: 18433484
18.  Traffic-Related Atmospheric Pollutants Levels during Pregnancy and Offspring’s Term Birth Weight: A Study Relying on a Land-Use Regression Exposure Model 
Environmental Health Perspectives  2007;115(9):1283-1292.
Background
Some studies have suggested that particulate matter (PM) levels during pregnancy may be associated with birth weight. Road traffic is a major source of fine PM (PM with aero-dynamic diameter < 2.5 μm; PM2.5).
Objective
We determined to characterize the influence of maternal exposure to atmospheric pollutants due to road traffic and urban activities on offspring term birth weight.
Methods
Women from a birth cohort [the LISA (Influences of Lifestyle Related Factors on the Human Immune System and Development of Allergies in Children) cohort] who delivered a non-premature baby with a birth weight > 2,500 g in Munich metropolitan area were included. We assessed PM2.5, PM2.5 absorbance (which depends on the blackness of PM2.5, a marker of traffic-related air pollution), and nitrogen dioxide levels using a land-use regression model, taking into account the type and length of roads, population density, land coverage around the home address, and temporal variations in pollution during pregnancy. Using Poisson regression, we estimated prevalence ratios (PR) of birth weight < 3,000 g, adjusted for gestational duration, sex, maternal smoking, height, weight, and education.
Results
Exposure was defined for 1,016 births. Taking the lowest quartile of exposure during pregnancy as a reference, the PR of birth weight < 3,000 g associated with the highest quartile was 1.7 for PM2.5 [95% confidence interval (CI), 1.2–2.7], 1.8 for PM2.5 absorbance (95% CI, 1.1–2.7), and 1.2 for NO2 (95% CI, 0.7–1.7). The PR associated with an increase of 1 μg/m3 in PM2.5 levels was 1.13 (95% CI, 1.00–1.29).
Conclusion
Increases in PM2.5 levels and PM2.5 absorbance were associated with decreases in term birth weight. Traffic-related air pollutants may have adverse effects on birth weight.
doi:10.1289/ehp.10047
PMCID: PMC1964922  PMID: 17805417
atmospheric pollution; birth weight; diesel soot; environment; geographic information system; intrauterine growth restriction; particulate matter; pregnancy; reproduction; road traffic; sensitivity analysis
19.  Traffic-Related Air Pollution and Otitis Media 
Environmental Health Perspectives  2006;114(9):1414-1418.
Background
Otitis media is one of the most common infections in young children. Although exposure to environmental tobacco smoke is a known risk factor associated with otitis media, little information is available regarding the potential association with air pollution.
Objective
We set out to study the relationship between exposure to traffic-related air pollution and otitis media in two birth cohorts.
Methods
Individual estimates of outdoor concentrations of traffic-related air pollutants—nitrogen dioxide, fine particles [particulate matter with aerodynamic diameters ≤ 2.5 μm (PM2.5)], and elemental carbon—were calculated for home addresses of approximately 3,700 and 650 infants from birth cohort studies in the Netherlands and Germany, respectively. Air pollution exposure was analyzed in relation to physician diagnosis of otitis media in the first 2 years of life.
Results
Odds ratios (adjusted for known major risk factors) for otitis media indicated positive associations with traffic-related air pollutants. An increase in 3 μg/m3 PM2.5, 0.5 μg/m3 elemental carbon, and 10 μg/m3 NO2 was associated with odds ratios of 1.13 (95% confidence interval, 1.00–1.27), 1.10 (1.00–1.22), and 1.14 (1.03–1.27) in the Netherlands and 1.24 (0.84–1.83), 1.10 (0.86–1.41), and 1.14 (0.87–1.49) in Germany, respectively.
Conclusions
These findings indicate an association between exposure to traffic-related air pollutants and the incidence of otitis media. Given the ubiquitous nature of air pollution exposure and the importance of otitis media to children’s health, these findings have significant public health implications.
doi:10.1289/ehp.9089
PMCID: PMC1570088  PMID: 16966098
air pollution; cohort studies; infant; otitis media; vehicle emissions
20.  Human serum metabolic profiles are age dependent 
Aging Cell  2012;11(6):960-967.
Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32–81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10−04 to 7.8 × 10−42, αcorr = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging.
doi:10.1111/j.1474-9726.2012.00865.x
PMCID: PMC3533791  PMID: 22834969
age; aging; epidemiology; metabolomics; population-based study

Results 1-20 (20)