Peter Lichtner

Publications (79)781.27 Total impact

• Article: SNCA: Major genetic modifier of age at onset of Parkinson's disease.

  Kathrin Brockmann, Claudia Schulte, Ann-Kathrin Hauser, Peter Lichtner, Heiko Huber, Walter Maetzler, Daniela Berg, Thomas Gasser
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  ABSTRACT: Age at onset serves as a predictor of progression and mortality in sporadic Parkinson's disease (PD). Therefore, the identification of genetic modifiers for age at onset might lead to a better understanding of disease pathogenesis. We performed multivariate linear regression analysis in 1396 sporadic PD patients assessing 21 single-nucleotide polymorphisms (SNPs) that have been previously suggested to be associated with sporadic PD. Moreover, a cumulative risk score was assigned to each patient and correlated with age at onset. We identified the rs356219 risk allele in the SNCA gene as significantly contributing to earlier age at onset. Neither one of the other 21 SNPs tested in this analysis nor the cumulative number of risk alleles showed a significant impact on PD onset. Because sequence variants in the SNCA gene are not only associated with autosomal dominantly inherited PD and increased susceptibility for sporadic PD but also have been found to modify the phenotype such as age at onset in both sporadic and various monogenic forms of PD, this gene serves as an outstanding target for further research on PD pathogenesis, which in return might provide potential therapeutic options. © 2013 Movement Disorder Society.
  Movement Disorders 05/2013; · 4.51 Impact Factor
• Source

  Available from: Irene Konstantopoulou

  Article: Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

  Montserrat Garcia-Closas, Fergus J Couch, Sara Lindstrom, Kyriaki Michailidou, Marjanka K Schmidt, Mark N Brook, Nick Orr, Suhn Kyong Rhie, Elio Riboli, Heather S Feigelson, [......], Alison M Dunning, Mark E Sherman, Georgia Chenevix-Trench, Stephen J Chanock, Per Hall, Paul D P Pharoah, Celine Vachon, Douglas F Easton, Christopher A Haiman, Peter Kraft
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  ABSTRACT: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
  Nature Genetics 03/2013; 45(4):392-398. · 35.53 Impact Factor
• Article: Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

  Kyriaki Michailidou, Per Hall, Anna Gonzalez-Neira, Maya Ghoussaini, Joe Dennis, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Stig E Bojesen, Manjeet K Bolla, [......], Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Jacques Simard, Montse Garcia-Closas, Paul D P Pharoah, Georgia Chenevix-Trench, Alison M Dunning, Javier Benitez, Douglas F Easton
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  ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
  Nature Genetics 03/2013; 45(4):353-361. · 35.53 Impact Factor
• Source

  Available from: Robert A Vierkant

  Article: Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

  Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, [......], Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning
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  ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
  Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
• Article: Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers.

  Juliet D French, Maya Ghoussaini, Stacey L Edwards, Kerstin B Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J Maranian, Martin O'Reilly, Kristine M Hillman, [......], Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J Schoemaker, Bruce A J Ponder, Heli Nevanlinna, Melissa A Brown, Georgia Chenevix-Trench, Douglas F Easton, Alison M Dunning
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  ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
  The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
• Article: The role of SCARB2 as susceptibility factor in Parkinson's disease.

  Franziska Hopfner, Eva C Schulte, Brit Mollenhauer, Benjamin Bereznai, Franziska Knauf, Peter Lichtner, Alexander Zimprich, Dietrich Haubenberger, Walter Pirker, Thomas Brücke, Annette Peters, Christian Gieger, Gregor Kuhlenbäumer, Claudia Trenkwalder, Juliane Winkelmann
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  ABSTRACT: BACKGROUND: Genetic variation in the glucocerebrosidase (GBA) gene is strongly associated with Parkinson's disease (PD). Transport of glucocerebrosidase to the lysosome involves the protein encoded by the SCARB2 gene. An association between the common SNP rs6812193, upstream of SCARB2, and PD has been reported previously. The role of exonic variants in the SCARB2 gene in PD has not been examined. METHODS: We studied the role of exonic variants in SCARB2 and tried to replicate the association between the SNP rs6812193 and PD in a German and Austrian sample. Screening of all SCARB2 exons by high-resolution melting curve analysis was performed in 376 German PD patients. The SNP rs6812193 was analyzed in 984 PD patients and 1014 general population controls. RESULTS: We identified no novel exonic variants in SCARB2 but confirmed the association between SNP rs6812193 and PD (OR, 0.86; P=.02). © 2013 Movement Disorder Society.
  Movement Disorders 02/2013; · 4.51 Impact Factor
• Source

  Available from: Rosa Peraita-Adrados

  Article: ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy.

  Juliette Faraco, Ling Lin, Birgitte Rahbek Kornum, Eimear E Kenny, Gosia Trynka, Mali Einen, Tom J Rico, Peter Lichtner, Yves Dauvilliers, Isabelle Arnulf, [......], Maxime Breban, Christian Gieger, Norman Klopp, Panos Deloukas, Cisca Wijmenga, Joachim Hallmayer, Suna Onengut-Gumuscu, Stephen S Rich, Juliane Winkelmann, Emmanuel Mignot
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  ABSTRACT: Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H () and Tumor necrosis factor (ligand) superfamily member 4 (, also called ), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.
  PLoS Genetics 02/2013; 9(2):e1003270. · 8.69 Impact Factor
• Source

  Available from: Manu Sharma

  Article: A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

  Manu Sharma, John P A Ioannidis, Jan O Aasly, Grazia Annesi, Alexis Brice, Lars Bertram, Maria Bozi, Maria Barcikowska, David Crosiers, Carl E Clarke, [......], Christine Van Broeckhoven, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Harumi S Yomono, Kuo-Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius Maraganore, Rejko Krüger
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  ABSTRACT: BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
  Journal of Medical Genetics 11/2012; 49(11):721-726. · 6.36 Impact Factor
• Article: A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.

  Afshan Siddiq, Fergus J Couch, Gary K Chen, Sara Lindström, Diana Eccles, Robert C Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, [......], Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon
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  ABSTRACT: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
  Human Molecular Genetics 09/2012; · 7.64 Impact Factor
• Article: Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis.

  Dorothea Buck, Eva Albrecht, Muhammad Aslam, An Goris, Natalie Hauenstein, Angela Jochim, Sabine Cepok, Verena Grummel, Bénédicte Dubois, Achim Berthele, Peter Lichtner, Christian Gieger, Juliane Winkelmann, Bernhard Hemmer
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  ABSTRACT: OBJECTIVE: Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS. METHODS: We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls. RESULTS: Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10(-11) to p = 7.5 × 10(-16) . All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r(2) range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set. INTERPRETATION: The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease. ANN NEUROL 2012.
  Annals of Neurology 09/2012; · 11.09 Impact Factor
• Article: Dilution of candidates: the case of iron-related genes in restless legs syndrome.

  Konrad Oexle, Barbara Schormair, Janina S Ried, Darina Czamara, Katharina Heim, Birgit Frauscher, Birgit Högl, Claudia Trenkwalder, G Martin Fiedler, Joachim Thiery, Peter Lichtner, Holger Prokisch, Michael Specht, Bertram Müller-Myhsok, Angela Döring, Christian Gieger, Annette Peters, H-Erich Wichmann, Thomas Meitinger, Juliane Winkelmann
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  ABSTRACT: Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.193.
  European journal of human genetics: EJHG 08/2012; · 3.56 Impact Factor
• Article: Large-scale replication and heterogeneity in Parkinson disease genetic loci

  Manu Sharma, John P A Ioannidis, Jan O Aasly, Grazia Annesi, Alexis Brice, Christine Van Broeckhoven, Lars Bertram, Maria Bozi, David Crosiers, Carl Clarke, [......], Hiroyuki Tomiyama, Ryan J Uitti, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Kuo-Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius Maraganore, Rejko Krüger
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  ABSTRACT: Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of
  Neurology 08/2012; 79:1-9. · 8.31 Impact Factor
• Article: Large-scale replication and heterogeneity in Parkinson disease genetic loci.

  Manu Sharma, John P A Ioannidis, Jan O Aasly, Grazia Annesi, Alexis Brice, Christine Van Broeckhoven, Lars Bertram, Maria Bozi, David Crosiers, Carl Clarke, [......], Hiroyuki Tomiyama, Ryan J Uitti, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Kuo-Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius Maraganore, Rejko Krüger
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  ABSTRACT: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
  Neurology 07/2012; 79(7):659-67. · 8.31 Impact Factor
• Article: Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease.

  Eva C Schulte, Brit Mollenhauer, Alexander Zimprich, Benjamin Bereznai, Peter Lichtner, Dietrich Haubenberger, Walter Pirker, Thomas Brücke, Maria J Molnar, Annette Peters, Christian Gieger, Claudia Trenkwalder, Juliane Winkelmann
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  ABSTRACT: Recently, mutations in eukaryotic translation initiation factor 4G1 (EIF4G1) were reported as a rare cause of familial Parkinson's disease (PD). We screened the 33 exons of EIF4G1 by high-resolution melting curve analysis for variants in our Central European cohort of 376 PD cases. Variant frequency was assessed in a total of 975 PD cases and 1,014 general population controls. Eight novel nonsynonymous and four synonymous variants were identified. In our cohort, novel and previously identified nonsynonymous variants were very rare. Although it is possible that our general population controls also comprise individuals who have or could develop PD in the future, the presence of the original mutation (EIF4G1 p.Arg1205 His) in three controls only, raises questions about the causality of this variant with regard to PD.
  Neurogenetics 06/2012; 13(3):281-5. · 3.35 Impact Factor
• Article: A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.

  Moritz F Sinner, Kimmo Porthan, Peter A Noseworthy, Aki S Havulinna, Jani T Tikkanen, Martina Müller-Nurasyid, Gina Peloso, Sheila Ulivi, Britt Maria Beckmann, A Catharina Brockhaus, [......], Barbara Thorand, H-Erich Wichmann, Gianfranco Sinagra, Jorma Viikari, Christopher J O'Donnell, Patrick T Ellinor, Heikki V Huikuri, Stefan Kääb, Christopher Newton-Cheh, Veikko Salomaa
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  ABSTRACT: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
  Heart rhythm: the official journal of the Heart Rhythm Society 06/2012; 9(10):1627-34. · 4.56 Impact Factor
• Article: Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients.

  Mascha C Schmied, Sonja Zehetmayer, Markus Reindl, Rainer Ehling, Barbara Bajer-Kornek, Fritz Leutmezer, Karin Zebenholzer, Christoph Hotzy, Peter Lichtner, Thomas Meitinger, [......], Klaus Huber, Michael Khalil, Sigrid Fuchs, Helena Schmidt, Eduard Auff, Wolfgang Kristoferitsch, Franz Fazekas, Thomas Berger, Karl Vass, Alexander Zimprich
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  ABSTRACT: We performed a replication study in 883 Austrian multiple sclerosis (MS) patients and 972 control individuals for 25 previously risk-associated loci (39 SNPs). Two loci, rs1109670 (DDEF2/MBOAT2, p < 0.02) and rs16914086 (TBC1D2, p < 0.05), are replicated here for the first time. Furthermore, we tested all 39 SNPs for association with age at disease onset and measures of disease severity. We observed a trend for association of rs3135388 (HLA-DRB1*1501, p < 0.01), rs7090530 (IL2RA, p < 0.026) and rs1841770 (ZIC1, p < 0.017) with a younger age at MS onset and of rs12044852 (CD58, p < 0.035) with shorter time to reach EDSS6.
  Neurogenetics 03/2012; 13(2):181-7. · 3.35 Impact Factor
• Source

  Available from: Anna Gonzalez-Neira

  Article: Genome-wide association analysis identifies three new breast cancer susceptibility loci.

  Maya Ghoussaini, Olivia Fletcher, Kyriaki Michailidou, Clare Turnbull, Marjanka K Schmidt, Ed Dicks, Joe Dennis, Qin Wang, Manjeet K Humphreys, Craig Luccarini, [......], Susan M Gerty, Nikki J Graham, Bruce A J Ponder, Georgia Chenevix-Trench, Paul D P Pharoah, Mark Lathrop, Alison M Dunning, Nazneen Rahman, Julian Peto, Douglas F Easton
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  ABSTRACT: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
  Nature Genetics 01/2012; 44(3):312-8. · 35.53 Impact Factor
• Article: A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.

  Stefan Kääb, Dana C Crawford, Moritz F Sinner, Elijah R Behr, Prince J Kannankeril, Arthur A M Wilde, Connie R Bezzina, Eric Schulze-Bahr, Pascale Guicheney, Nanette H Bishopric, [......], Thomas Meitinger, Annette Peters, H-Erich Wichmann, Christiana Ingram, Yuki Bradford, Shannon Carter, Kris Norris, Marylyn D Ritchie, Alfred L George, Dan M Roden
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  ABSTRACT: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
  Circulation Cardiovascular Genetics 11/2011; 5(1):91-9. · 6.11 Impact Factor
• Article: Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury.

  Jochen D Muehlschlegel, Tjörvi E Perry, Kuang-Yu Liu, Amanda A Fox, Shane A Smith, Peter Lichtner, Charles D Collard, Stanton K Shernan, John H Hartwig, Simon C Body, Karin M Hoffmeister
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  ABSTRACT: Protease-activated receptors (PAR)-1 and -4 are the principal receptors for thrombin-mediated platelet activation. Functional genetic variation has been described in the human PAR1 gene, but not in the PAR4 gene (F2RL3). We sought to identify variants in and around F2RL3 and to determine their association with perioperative myocardial injury (PMI) after coronary artery bypass graft surgery. We further explored possible mechanisms for F2RL3 single nucleotide polymorphism (SNP) associations with PMI including altered receptor expression and platelet activation. Twenty-three SNPs in the F2RL3 gene region were genotyped in two phases in 934 Caucasian subjects. Platelets from 43 subjects (23 major allele, 20 risk allele) homozygous for rs773857 (SNP with the strongest association with PMI) underwent flow cytometry to assess PAR4 receptor number and response to activation by a specific PAR4 activating peptide (AYPGKF) measured by von Willebrand factor (vWf) binding and P-selectin release and PAC-1 binding. We identified a novel association of SNP rs773857 with PMI (OR = 2.4, P = 0.004). rs773857 risk allele homozygotes have significantly increased platelet counts and platelets showed a significant increase in P-selectin release after activation (P = 0.004). We conclude that rs773857 risk allele homozygotes are associated with risk for increased platelet count and hyperactivity. Am. J. Hematol. 2011. © 2011 Wiley Periodicals, Inc.
  American Journal of Hematology 11/2011; · 4.67 Impact Factor
• Article: Correction: genome-wide association study identifies novel restless legs syndrome susceptibility Loci on 2p14 and 16q12.1.

  Juliane Winkelmann, Darina Czamara, Barbara Schormair, Franziska Knauf, Eva C Schulte, Claudia Trenkwalder, Yves Dauvilliers, Olli Polo, Birgit Högl, Klaus Berger, [......], Holger Prokisch, Peter Lichtner, Paul Peppard, Juliette Faraco, Emmanuel Mignot, Christian Gieger, Thomas Illig, H-Erich Wichmann, Bertram Müller-Myhsok, Thomas Meitinger
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  ABSTRACT: [This corrects the article on p. e1002171 in vol. 7.].
  PLoS Genetics 08/2011; 7(8). · 8.69 Impact Factor