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1.  Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation 
Andlauer, Till F. M. | Buck, Dorothea | Antony, Gisela | Bayas, Antonios | Bechmann, Lukas | Berthele, Achim | Chan, Andrew | Gasperi, Christiane | Gold, Ralf | Graetz, Christiane | Haas, Jürgen | Hecker, Michael | Infante-Duarte, Carmen | Knop, Matthias | Kümpfel, Tania | Limmroth, Volker | Linker, Ralf A. | Loleit, Verena | Luessi, Felix | Meuth, Sven G. | Mühlau, Mark | Nischwitz, Sandra | Paul, Friedemann | Pütz, Michael | Ruck, Tobias | Salmen, Anke | Stangel, Martin | Stellmann, Jan-Patrick | Stürner, Klarissa H. | Tackenberg, Björn | Then Bergh, Florian | Tumani, Hayrettin | Warnke, Clemens | Weber, Frank | Wiendl, Heinz | Wildemann, Brigitte | Zettl, Uwe K. | Ziemann, Ulf | Zipp, Frauke | Arloth, Janine | Weber, Peter | Radivojkov-Blagojevic, Milena | Scheinhardt, Markus O. | Dankowski, Theresa | Bettecken, Thomas | Lichtner, Peter | Czamara, Darina | Carrillo-Roa, Tania | Binder, Elisabeth B. | Berger, Klaus | Bertram, Lars | Franke, Andre | Gieger, Christian | Herms, Stefan | Homuth, Georg | Ising, Marcus | Jöckel, Karl-Heinz | Kacprowski, Tim | Kloiber, Stefan | Laudes, Matthias | Lieb, Wolfgang | Lill, Christina M. | Lucae, Susanne | Meitinger, Thomas | Moebus, Susanne | Müller-Nurasyid, Martina | Nöthen, Markus M. | Petersmann, Astrid | Rawal, Rajesh | Schminke, Ulf | Strauch, Konstantin | Völzke, Henry | Waldenberger, Melanie | Wellmann, Jürgen | Porcu, Eleonora | Mulas, Antonella | Pitzalis, Maristella | Sidore, Carlo | Zara, Ilenia | Cucca, Francesco | Zoledziewska, Magdalena | Ziegler, Andreas | Hemmer, Bernhard | Müller-Myhsok, Bertram
Science Advances  2016;2(6):e1501678.
Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.
We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
doi:10.1126/sciadv.1501678
PMCID: PMC4928990  PMID: 27386562
Multiple sclerosis; genome-wide association study; DNA methylation; L3MBTL3; MAZ; ERG; DLEU1; SHMT1
2.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
BACKGROUND
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
doi:10.1016/j.biopsych.2014.08.027
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
3.  Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk 
Lin, Wei-Yu | Camp, Nicola J. | Ghoussaini, Maya | Beesley, Jonathan | Michailidou, Kyriaki | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Th Rutgers, Emiel J. | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Peto, Julian | Dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Sawyer, Elinor J. | Cheng, Timothy | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Marmé, Frederik | Surowy, Harald M. | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Mulot, Claire | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Anton-Culver, Hoda | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Horio, Akiyo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Neven, Patrick | Wauters, Els | Wildiers, Hans | Lambrechts, Diether | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Purrington, Kristen | Giles, Graham G. | Milne, Roger L. | Mclean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Teo, Soo Hwang | Yip, Cheng Har | Hassan, Norhashimah | Vithana, Eranga Nishanthie | Kristensen, Vessela | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | García-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Hooning, Maartje J. | Hollestelle, Antoinette | Van Den Ouweland, Ans M.W. | Jager, Agnes | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cross, Simon S. | Reed, Malcolm W. R. | Blot, William | Signorello, Lisa B. | Cai, Qiuyin | Pharoah, Paul D.P. | Perkins, Barbara | Shah, Mitul | Blows, Fiona M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Putti, Thomas Choudary | Hamann, Ute | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-ling | Ashworth, Alan | Jones, Michael | Orr, Nick | Swerdlow, Anthony J | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel F. | Bui, Quang M. | Chanock, Stephen J. | Hunter, David J. | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Muranen, Taru A. | Heikkinen, Tuomas | Irwanto, Astrid | Rahman, Nazneen | Turnbull, Clare A. | Waisfisz, Quinten | Meijers-Heijboer, Hanne E. J. | Adank, Muriel A. | Van Der Luijt, Rob B. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison | Easton, Douglas F. | Cox, Angela
Human Molecular Genetics  2014;24(1):285-298.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 10−5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 10−9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
doi:10.1093/hmg/ddu431
PMCID: PMC4334820  PMID: 25168388
4.  XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans 
Neuropsychopharmacology  2014;40(2):361-371.
Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80—the homolog of mammalian XRCC5—due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.
doi:10.1038/npp.2014.178
PMCID: PMC4443948  PMID: 25035082
5.  Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma 
Cancer Medicine  2015;4(11):1700-1704.
The Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett’s esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett’s esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P <  10−4 in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10−5) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.
doi:10.1002/cam4.500
PMCID: PMC4673997  PMID: 26383589
BARX1; esophageal adenocarcinoma; FOXF1; FOXP1; genetic association study
6.  A genome-wide association study points to multiple loci predicting antidepressant treatment outcome in depression 
Archives of general psychiatry  2009;66(9):966-975.
Context
Efficacy of antidepressant treatment in depression is unsatisfactory as one in three patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome.
Objective
To identify genetic and clinical determinants of antidepressant treatment outcome in depression.
Design
Genome-wide pharmacogenetic association study with two independent replication samples.
Setting
We performed a genome-wide association (GWA) study in patients from the Munich-Antidepressant-Response-Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single nucleotide polymorphisms (SNPs) highly related to outcome in both GWA studies was genotyped in a sample of the Sequenced-Treatment-Alternatives-to-Relieve-Depression (STAR*D) study.
Participants
339 inpatients suffering from a depressive episode (MARS sample), further 361 depressed inpatients (German replication sample), and 832 outpatients with major depression (STAR*D sample).
Main Outcome Measures
We generated a multi-locus genetic variable describing the individual number of alleles of the selected SNPs associated with beneficial treatment outcome in the MARS sample (“response” alleles) to evaluate additive genetic effects on antidepressant treatment outcome.
Results
Multi-locus analysis revealed a significant contribution of a binary variable categorizing patients as carriers of a high vs. low number of response alleles in predicting antidepressant treatment outcome in both samples, MARS and STAR*D. In addition, we observed that patients with a comorbid anxiety disorder in combination with a low number of response alleles showed the least favorable outcome.
Conclusion
Our results demonstrate the importance of multiple genetic factors in combination with clinical features to predict antidepressant treatment outcome underscoring the multifactorial nature of this trait.
doi:10.1001/archgenpsychiatry.2009.95
PMCID: PMC4465570  PMID: 19736353
7.  Analyzing pathways from childhood maltreatment to internalizing symptoms and disorders in children and adolescents (AMIS): a study protocol 
BMC Psychiatry  2015;15:126.
Background
Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders.
Methods/design
Four large samples amounting to a total of N = 920 children aged 4–16 years will be assessed: Two cohorts with prior internalizing psychopathology and controls will be checked for maltreatment and two cohorts with substantiated maltreatment will be checked for internalizing (and externalizing) psychopathology. We will apply a multi-source (interview, questionnaires, official records), multi-informant strategy (parents, children, teachers) to assess maltreatment characteristics (e.g., subtypes, developmental timing, chronicity) and psychopathological symptoms, supplemented with multiple measurements of risk and protective factors and cutting-edge laboratory analyses of endocrine, steroid metabolomic and epigenetic factors. As previous assessments in the two largest samples are already available, longitudinal data will be generated within the three year study period.
Discussion
Our results will lay the empirical foundation for (a) detection of early biopsychosocial markers, (b) development of screening measures, and (c) multisystem-oriented interventions in the wake of maltreatment.
doi:10.1186/s12888-015-0512-z
PMCID: PMC4460761  PMID: 26058452
Maltreatment; Developmental psychopathology; Internalizing disorders; Developmental pathways; Neuroendocrine functioning; HPA axis; Gene-environment interaction; Cognitive-emotional strategies
8.  Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders 
Neuron  2015;86(5):1189-1202.
Summary
Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.
Video Abstract
Highlights
•SNPs in long-range enhancers alter the transcriptional response of GR target genes•These functional SNPs predict risk for psychiatric but not other medical disorders•These variants are associated with differential neural circuit responses to threat•GR transcripts are strongly co-expressed and regulated in the brain of animal models
Using a stimulated eQTL approach, Arloth et al. show that common genetic variants that alter the initial transcriptome response to stress hormone receptor activation also cumulatively increase the risk for stress-related psychiatric disorders and predict a threat response from the amygdala.
doi:10.1016/j.neuron.2015.05.034
PMCID: PMC4490780  PMID: 26050039
9.  Connecting Anxiety and Genomic Copy Number Variation: A Genome-Wide Analysis in CD-1 Mice 
PLoS ONE  2015;10(5):e0128465.
Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional array-based genotyping approaches, we detected CNVs in a mouse model consisting of two inbred mouse lines showing high (HAB) and low (LAB) anxiety-related behavior, respectively. An influence of CNVs on gene expression in the central (CeA) and basolateral (BLA) amygdala, paraventricular nucleus (PVN), and cingulate cortex (Cg) was shown by a two-proportion Z-test (p = 1.6 x 10-31), with a positive correlation in the CeA (p = 0.0062), PVN (p = 0.0046) and Cg (p = 0.0114), indicating a contribution of CNVs to the genetic predisposition to trait anxiety in the specific context of HAB/LAB mice. In order to confirm anxiety-relevant CNVs and corresponding genes in a second mouse model, we further examined CD-1 outbred mice. We revealed the distribution of CNVs by genotyping 64 CD 1 individuals using a high-density genotyping array (Jackson Laboratory). 78 genes within those CNVs were identified to show nominally significant association (48 genes), or a statistical trend in their association (30 genes) with the time animals spent on the open arms of the elevated plus-maze (EPM). Fifteen of them were considered promising candidate genes of anxiety-related behavior as we could show a significant overlap (permutation test, p = 0.0051) with genes within HAB/LAB CNVs. Thus, here we provide what is to our knowledge the first extensive catalogue of CNVs in CD-1 mice and potential corresponding candidate genes linked to anxiety-related behavior in mice.
doi:10.1371/journal.pone.0128465
PMCID: PMC4444327  PMID: 26011321
10.  Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort 
Dyslexia is one of the most common childhood disorders with a prevalence of around 5–10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children – the NeuroDys cohort – that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case–control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case–control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects.
doi:10.1038/ejhg.2013.199
PMCID: PMC3992562  PMID: 24022301
dyslexia; word-reading; spelling; association study; candidate genes
11.  A genetic risk score combining 32 SNPs is associated with body mass index and improves obesity prediction in people with major depressive disorder 
BMC Medicine  2015;13:86.
Background
Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD.
Methods
Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case–control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity.
Results
In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P <0.001) but explained only a modest amount of variance. Adding ‘traditional’ risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62–0.68; χ2 = 27.68; P <0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68–0.73; χ2 = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results.
Conclusions
A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0334-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0334-3
PMCID: PMC4407390  PMID: 25903154
Body mass index; Genetic risk score; Major depressive disorder; Obesity
12.  Common genetic variants influence human subcortical brain structures 
Hibar, Derrek P. | Stein, Jason L. | Renteria, Miguel E. | Arias-Vasquez, Alejandro | Desrivières, Sylvane | Jahanshad, Neda | Toro, Roberto | Wittfeld, Katharina | Abramovic, Lucija | Andersson, Micael | Aribisala, Benjamin S. | Armstrong, Nicola J. | Bernard, Manon | Bohlken, Marc M. | Boks, Marco P. | Bralten, Janita | Brown, Andrew A. | Chakravarty, M. Mallar | Chen, Qiang | Ching, Christopher R. K. | Cuellar-Partida, Gabriel | den Braber, Anouk | Giddaluru, Sudheer | Goldman, Aaron L. | Grimm, Oliver | Guadalupe, Tulio | Hass, Johanna | Woldehawariat, Girma | Holmes, Avram J. | Hoogman, Martine | Janowitz, Deborah | Jia, Tianye | Kim, Sungeun | Klein, Marieke | Kraemer, Bernd | Lee, Phil H. | Olde Loohuis, Loes M. | Luciano, Michelle | Macare, Christine | Mather, Karen A. | Mattheisen, Manuel | Milaneschi, Yuri | Nho, Kwangsik | Papmeyer, Martina | Ramasamy, Adaikalavan | Risacher, Shannon L. | Roiz-Santiañez, Roberto | Rose, Emma J. | Salami, Alireza | Sämann, Philipp G. | Schmaal, Lianne | Schork, Andrew J. | Shin, Jean | Strike, Lachlan T. | Teumer, Alexander | van Donkelaar, Marjolein M. J. | van Eijk, Kristel R. | Walters, Raymond K. | Westlye, Lars T. | Whelan, Christopher D. | Winkler, Anderson M. | Zwiers, Marcel P. | Alhusaini, Saud | Athanasiu, Lavinia | Ehrlich, Stefan | Hakobjan, Marina M. H. | Hartberg, Cecilie B. | Haukvik, Unn K. | Heister, Angelien J. G. A. M. | Hoehn, David | Kasperaviciute, Dalia | Liewald, David C. M. | Lopez, Lorna M. | Makkinje, Remco R. R. | Matarin, Mar | Naber, Marlies A. M. | McKay, D. Reese | Needham, Margaret | Nugent, Allison C. | Pütz, Benno | Royle, Natalie A. | Shen, Li | Sprooten, Emma | Trabzuni, Daniah | van der Marel, Saskia S. L. | van Hulzen, Kimm J. E. | Walton, Esther | Wolf, Christiane | Almasy, Laura | Ames, David | Arepalli, Sampath | Assareh, Amelia A. | Bastin, Mark E. | Brodaty, Henry | Bulayeva, Kazima B. | Carless, Melanie A. | Cichon, Sven | Corvin, Aiden | Curran, Joanne E. | Czisch, Michael | de Zubicaray, Greig I. | Dillman, Allissa | Duggirala, Ravi | Dyer, Thomas D. | Erk, Susanne | Fedko, Iryna O. | Ferrucci, Luigi | Foroud, Tatiana M. | Fox, Peter T. | Fukunaga, Masaki | Gibbs, J. Raphael | Göring, Harald H. H. | Green, Robert C. | Guelfi, Sebastian | Hansell, Narelle K. | Hartman, Catharina A. | Hegenscheid, Katrin | Heinz, Andreas | Hernandez, Dena G. | Heslenfeld, Dirk J. | Hoekstra, Pieter J. | Holsboer, Florian | Homuth, Georg | Hottenga, Jouke-Jan | Ikeda, Masashi | Jack, Clifford R. | Jenkinson, Mark | Johnson, Robert | Kanai, Ryota | Keil, Maria | Kent, Jack W. | Kochunov, Peter | Kwok, John B. | Lawrie, Stephen M. | Liu, Xinmin | Longo, Dan L. | McMahon, Katie L. | Meisenzahl, Eva | Melle, Ingrid | Mohnke, Sebastian | Montgomery, Grant W. | Mostert, Jeanette C. | Mühleisen, Thomas W. | Nalls, Michael A. | Nichols, Thomas E. | Nilsson, Lars G. | Nöthen, Markus M. | Ohi, Kazutaka | Olvera, Rene L. | Perez-Iglesias, Rocio | Pike, G. Bruce | Potkin, Steven G. | Reinvang, Ivar | Reppermund, Simone | Rietschel, Marcella | Romanczuk-Seiferth, Nina | Rosen, Glenn D. | Rujescu, Dan | Schnell, Knut | Schofield, Peter R. | Smith, Colin | Steen, Vidar M. | Sussmann, Jessika E. | Thalamuthu, Anbupalam | Toga, Arthur W. | Traynor, Bryan J. | Troncoso, Juan | Turner, Jessica A. | Valdés Hernández, Maria C. | van ’t Ent, Dennis | van der Brug, Marcel | van der Wee, Nic J. A. | van Tol, Marie-Jose | Veltman, Dick J. | Wassink, Thomas H. | Westman, Eric | Zielke, Ronald H. | Zonderman, Alan B. | Ashbrook, David G. | Hager, Reinmar | Lu, Lu | McMahon, Francis J. | Morris, Derek W. | Williams, Robert W. | Brunner, Han G. | Buckner, Randy L. | Buitelaar, Jan K. | Cahn, Wiepke | Calhoun, Vince D. | Cavalleri, Gianpiero L. | Crespo-Facorro, Benedicto | Dale, Anders M. | Davies, Gareth E. | Delanty, Norman | Depondt, Chantal | Djurovic, Srdjan | Drevets, Wayne C. | Espeseth, Thomas | Gollub, Randy L. | Ho, Beng-Choon | Hoffmann, Wolfgang | Hosten, Norbert | Kahn, René S. | Le Hellard, Stephanie | Meyer-Lindenberg, Andreas | Müller-Myhsok, Bertram | Nauck, Matthias | Nyberg, Lars | Pandolfo, Massimo | Penninx, Brenda W. J. H. | Roffman, Joshua L. | Sisodiya, Sanjay M. | Smoller, Jordan W. | van Bokhoven, Hans | van Haren, Neeltje E. M. | Völzke, Henry | Walter, Henrik | Weiner, Michael W. | Wen, Wei | White, Tonya | Agartz, Ingrid | Andreassen, Ole A. | Blangero, John | Boomsma, Dorret I. | Brouwer, Rachel M. | Cannon, Dara M. | Cookson, Mark R. | de Geus, Eco J. C. | Deary, Ian J. | Donohoe, Gary | Fernández, Guillén | Fisher, Simon E. | Francks, Clyde | Glahn, David C. | Grabe, Hans J. | Gruber, Oliver | Hardy, John | Hashimoto, Ryota | Hulshoff Pol, Hilleke E. | Jönsson, Erik G. | Kloszewska, Iwona | Lovestone, Simon | Mattay, Venkata S. | Mecocci, Patrizia | McDonald, Colm | McIntosh, Andrew M. | Ophoff, Roel A. | Paus, Tomas | Pausova, Zdenka | Ryten, Mina | Sachdev, Perminder S. | Saykin, Andrew J. | Simmons, Andy | Singleton, Andrew | Soininen, Hilkka | Wardlaw, Joanna M. | Weale, Michael E. | Weinberger, Daniel R. | Adams, Hieab H. H. | Launer, Lenore J. | Seiler, Stephan | Schmidt, Reinhold | Chauhan, Ganesh | Satizabal, Claudia L. | Becker, James T. | Yanek, Lisa | van der Lee, Sven J. | Ebling, Maritza | Fischl, Bruce | Longstreth, W. T. | Greve, Douglas | Schmidt, Helena | Nyquist, Paul | Vinke, Louis N. | van Duijn, Cornelia M. | Xue, Luting | Mazoyer, Bernard | Bis, Joshua C. | Gudnason, Vilmundur | Seshadri, Sudha | Ikram, M. Arfan | Martin, Nicholas G. | Wright, Margaret J. | Schumann, Gunter | Franke, Barbara | Thompson, Paul M. | Medland, Sarah E.
Nature  2015;520(7546):224-229.
The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
doi:10.1038/nature14101
PMCID: PMC4393366  PMID: 25607358
13.  A Genome-wide Association Study of Early-onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age 
Ahsan, Habibul | Halpern, Jerry | Kibriya, Muhammad G | Pierce, Brandon L | Tong, Lin | Gamazon, Eric | McGuire, Valerie | Felberg, Anna | Shi, Jianxin | Jasmine, Farzana | Roy, Shantanu | Brutus, Rachelle | Argos, Maria | Melkonian, Stephanie | Chang-Claude, Jenny | Andrulis, Irene | Hopper, John L | John, Esther M. | Malone, Kathi | Ursin, Giske | Gammon, Marilie D | Thomas, Duncan C | Seminara, Daniela | Casey, Graham | Knight, Julia A | Southey, Melissa C | Giles, Graham G | Santella, Regina M | Lee, Eunjung | Conti, David | Duggan, David | Gallinger, Steve | Haile, Robert | Jenkins, Mark | Lindor, Noralane M | Newcomb, Polly | Michailidou, Kyriaki | Apicella, Carmel | Park, Daniel J | Peto, Julian | Fletcher, Olivia | Silva, Isabel dos Santos | Lathrop, Mark | Hunter, David J | Chanock, Stephen J | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lochmann, Magdalena | Beckmann, Lars | Hein, Rebecca | Makalic, Enes | Schmidt, Daniel F | Bui, Quang Minh | Stone, Jennifer | Flesch-Janys, Dieter | Dahmen, Norbert | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Hall, Per | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Rahman, Nazneen | Turnbull, Clare | Dunning, Alison M. | Pharoah, Paul | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Uitterlinden, Andre G. | Rivadeneira, Fernando | Nicolae, Dan | Easton, Douglas F | Cox, Nancy J | Whittemore, Alice S
Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 SNPs among a discovery set of 3,523 EOBC incident case and 2,702 population control women aged <=51 years. The SNPs with smallest P-values were examined in a replication set of 3,470 EOBC case and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P-values to obtain a gene-based P-value. We examined the gene with smallest P-value for replication in 1,145 breast cancer case and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P<4×10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P<6×10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P<0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genomewide gene-based threshold of 2.5×10−6. In conclusion, EOBC and LOBC appear to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
doi:10.1158/1055-9965.EPI-13-0340
PMCID: PMC3990360  PMID: 24493630
14.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Summary
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
doi:10.1038/nature13595
PMCID: PMC4112379  PMID: 25056061
15.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
16.  Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels 
Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9 × 10−5) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.
doi:10.1016/j.euroneuro.2012.08.010
PMCID: PMC4221661  PMID: 23026132
Depression; Leptin; Treatment response; Gene expression; Pharmacogenetics
17.  The Challenges of Genome-Wide Interaction Studies: Lessons to Learn from the Analysis of HDL Blood Levels 
PLoS ONE  2014;9(10):e109290.
Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10−8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.
doi:10.1371/journal.pone.0109290
PMCID: PMC4203717  PMID: 25329471
18.  Blood cis-eQTL Analysis Fails to Identify Novel Association Signals among Sub-Threshold Candidates from Genome-Wide Association Studies in Restless Legs Syndrome 
PLoS ONE  2014;9(5):e98092.
Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal<10−3 were identified, while in 976 individuals belonging to the SHIP-TREND general population study 53 cis-eQTLs with pnominal<10−3 were present. 23 of these cis-eQTLs overlapped between the two cohorts. Subsequently, the twelve of the 23 cis-eQTL SNPs, which were not located at an already published RLS-associated locus, were tested for association in 2449 RLS cases and 1462 controls. The top SNP, located in the DET1 gene, was nominally significant (p<0.05) but did not withstand correction for multiple testing (p = 0.42). Although a similar approach has been used successfully with regard to other complex diseases, we were unable to identify new genetic susceptibility factor for RLS by adding this novel level of functional assessment to RLS GWAS data.
doi:10.1371/journal.pone.0098092
PMCID: PMC4038519  PMID: 24875634
19.  Clinically Apparent and Occult Metastasized Seminoma: Almost Indistinguishable on the Transcriptional Level 
PLoS ONE  2014;9(5):e95009.
Purpose
The aim of the present study was to examine the biological differences between seminomas with occult and clinically apparent metastases at the time of diagnosis of the primary tumor to gain insight into the biology of these tumors and facilitate the identification of novel predictors of seminoma metastasis.
Materials and Methods
Total RNA including small RNAs was isolated from testicular tumors of patients with pure seminoma presenting with lymphogenic metastasis (n = 5, clinical stage IIb/c) and occult metastasis (n = 5, clinical stage I). The regulation of biological processes was examined (1) throughout the mRNA transcriptome (whole genome microarrays, 8×60 K Array, Agilent with 4 samples/group) and (2) the miRNA transcriptome employing small RNA next generation sequencing (SOLID, Life Technologies with 5 samples/group). Protein coding genes (mRNAs) and small RNAs showing a significant (≥2-fold) difference between the groups were identified. Finally (3), we examined 95 candidate miRNAs in 36 apparent metastasized and another 5 occult metastasized seminoma using logistic regression analysis.
Results
Among 19,596 genes, on average 12,894 mRNAs appeared expressed (65.8%, SD+/−2.4; range, 62.0–69.3%) and 16.99×106/13.94×106 small RNA reads were identified for apparent/occult metastasized seminoma. These reads on average convert into 9,901/9,675 small RNAs including 422/404 mature microRNAs. None of these mRNAs/small RNAs met our selection criteria for candidate genes. From 95 candidate miRNAs 44 appeared expressed, with 3 of them showing weak but significant (p = 0.05) differences among both groups.
Conclusions
Occult and apparent metastasized seminomas are biologically almost indistinguishable and probably represent no separate tumor entities. These findings may simplify future research on seminoma metastasis.
doi:10.1371/journal.pone.0095009
PMCID: PMC4006798  PMID: 24788992
20.  Genome-wide linkage analysis is a powerful prenatal diagnostic tool in families with unknown genetic defects 
Genome-wide linkage analysis is an established tool to map inherited diseases. To our knowledge it has not been used in prenatal diagnostics of any genetic disorder. We present a family with a severe recessive mental retardation syndrome, where the mother wished pregnancy termination to avoid delivering another affected child. By genome-wide scanning using the Affymetrix (Santa Clara, CA, USA) 10k chip we were able to establish the disease haplotype. Without knowing the exact genetic defect, we excluded the condition in the fetus. The woman finally gave birth to a healthy baby. We suggest that genome-wide linkage analysis – based on either SNP mapping or full-genome sequencing – is a very useful tool in prenatal diagnostics of diseases.
doi:10.1038/ejhg.2012.198
PMCID: PMC3598323  PMID: 23032112
linkage analysis; prenatal diagnostics; mental retardation
21.  Dilution of candidates: the case of iron-related genes in restless legs syndrome 
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.
doi:10.1038/ejhg.2012.193
PMCID: PMC3598324  PMID: 22929029
restless legs syndrome; iron parameters; MEIS1 haplotype; power calculation; linear regression; logistic regression
22.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk 
Michailidou, Kyriaki | Hall, Per | Gonzalez-Neira, Anna | Ghoussaini, Maya | Dennis, Joe | Milne, Roger L | Schmidt, Marjanka K | Chang-Claude, Jenny | Bojesen, Stig E | Bolla, Manjeet K | Wang, Qin | Dicks, Ed | Lee, Andrew | Turnbull, Clare | Rahman, Nazneen | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | Silva, Isabel dos Santos | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel | van der Luijt, Rob B | Hein, Rebecca | Dahmen, Norbert | Beckman, Lars | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Hopper, John L | Southey, Melissa C | Makalic, Enes | Schmidt, Daniel F | Uitterlinden, Andre G | Hofman, Albert | Hunter, David J | Chanock, Stephen J | Vincent, Daniel | Bacot, François | Tessier, Daniel C | Canisius, Sander | Wessels, Lodewyk F A | Haiman, Christopher A | Shah, Mitul | Luben, Robert | Brown, Judith | Luccarini, Craig | Schoof, Nils | Humphreys, Keith | Li, Jingmei | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Couch, Fergus J | Wang, Xianshu | Vachon, Celine | Stevens, Kristen N | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Johnson, Nichola | Aitken, Zoe | Aaltonen, Kirsimari | Heikkinen, Tuomas | Broeks, Annegien | Van’t Veer, Laura J | van der Schoot, C Ellen | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Menegaux, Florence | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Zamora, M Pilar | Perez, Jose Ignacio Arias | Pita, Guillermo | Alonso, M Rosario | Cox, Angela | Brock, Ian W | Cross, Simon S | Reed, Malcolm W R | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J | Hollestelle, Antoinette | van den Ouweland, Ans M W | Jager, Agnes | Bui, Quang M | Stone, Jennifer | Dite, Gillian S | Apicella, Carmel | Tsimiklis, Helen | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Devilee, Peter | Tollenaar, Rob A E M | Seynaeve, Caroline | van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Bogdanova, Natalia V | Antonenkova, Natalia N | Dörk, Thilo | Kristensen, Vessela N | Anton-Culver, Hoda | Slager, Susan | Toland, Amanda E | Edge, Stephen | Fostira, Florentia | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Sueta, Aiko | Wu, Anna H | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Teo, Soo Hwang | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Sng, Jen-Hwei | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-Ling | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Blot, William J | Signorello, Lisa B | Cai, Qiuyin | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Simard, Jacques | Garcia-Closas, Montse | Pharoah, Paul D P | Chenevix-Trench, Georgia | Dunning, Alison M | Benitez, Javier | Easton, Douglas F
Nature genetics  2013;45(4):353-361e2.
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.
doi:10.1038/ng.2563
PMCID: PMC3771688  PMID: 23535729
23.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci 
Garcia-Closas, Montserrat | Couch, Fergus J | Lindstrom, Sara | Michailidou, Kyriaki | Schmidt, Marjanka K | Brook, Mark N | orr, Nick | Rhie, Suhn Kyong | Riboli, Elio | Feigelson, Heather s | Le Marchand, Loic | Buring, Julie E | Eccles, Diana | Miron, Penelope | Fasching, Peter A | Brauch, Hiltrud | Chang-Claude, Jenny | Carpenter, Jane | Godwin, Andrew K | Nevanlinna, Heli | Giles, Graham G | Cox, Angela | Hopper, John L | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Dicks, Ed | Howat, Will J | Schoof, Nils | Bojesen, Stig E | Lambrechts, Diether | Broeks, Annegien | Andrulis, Irene L | Guénel, Pascal | Burwinkel, Barbara | Sawyer, Elinor J | Hollestelle, Antoinette | Fletcher, Olivia | Winqvist, Robert | Brenner, Hermann | Mannermaa, Arto | Hamann, Ute | Meindl, Alfons | Lindblom, Annika | Zheng, Wei | Devillee, Peter | Goldberg, Mark S | Lubinski, Jan | Kristensen, Vessela | Swerdlow, Anthony | Anton-Culver, Hoda | Dörk, Thilo | Muir, Kenneth | Matsuo, Keitaro | Wu, Anna H | Radice, Paolo | Teo, Soo Hwang | Shu, Xiao-Ou | Blot, William | Kang, Daehee | Hartman, Mikael | Sangrajrang, Suleeporn | Shen, Chen-Yang | Southey, Melissa C | Park, Daniel J | Hammet, Fleur | Stone, Jennifer | Veer, Laura J Van’t | Rutgers, Emiel J | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Peto, Julian | Schrauder, Michael G | Ekici, Arif B | Beckmann, Matthias W | Silva, Isabel dos Santos | Johnson, Nichola | Warren, Helen | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Lichtner, Peter | Lochmann, Magdalena | Justenhoven, Christina | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Greco, Dario | Heikkinen, Tuomas | Ito, Hidemi | Iwata, Hiroji | Yatabe, Yasushi | Antonenkova, Natalia N | Margolin, Sara | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Balleine, Rosemary | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Neven, Patrick | Dieudonné, Anne-Sophie | Leunen, Karin | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Peterlongo, Paolo | Peissel, Bernard | Bernard, Loris | Olson, Janet E | Wang, Xianshu | Stevens, Kristen | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona | Coetzee, Gerhard A | Feng, Ye | Henderson, Brian E | Schumacher, Fredrick | Bogdanova, Natalia V | Labrèche, France | Dumont, Martine | Yip, Cheng Har | Taib, Nur Aishah Mohd | Cheng, Ching-Yu | Shrubsole, Martha | Long, Jirong | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Tollenaar, Robertus A E M | Seynaeve, Caroline M | Kriege, Mieke | Hooning, Maartje J | Van den Ouweland, Ans M W | Van Deurzen, Carolien H M | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Balasubramanian, Sabapathy P | Cross, Simon S | Reed, Malcolm W R | Signorello, Lisa | Cai, Qiuyin | Shah, Mitul | Miao, Hui | Chan, Ching Wan | Chia, Kee Seng | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Hsiung, Chia-Ni | Wu, Pei-Ei | Yu, Jyh-Cherng | Ashworth, Alan | Jones, Michael | Tessier, Daniel C | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Vincent, Daniel | Bacot, Francois | Ambrosone, Christine B | Bandera, Elisa V | John, Esther M | Chen, Gary K | Hu, Jennifer J | Rodriguez-gil, Jorge L | Bernstein, Leslie | Press, Michael F | Ziegler, Regina G | Millikan, Robert M | Deming-Halverson, Sandra L | Nyante, Sarah | Ingles, Sue A | Waisfisz, Quinten | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Gibson, Lorna | Müller-Myhsok, Bertram | Schmutzler, Rita K | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Turnbull, Clare | Rahman, Nazneen | Meijers-Heijboer, Hanne | Uitterlinden, Andre G | Rivadeneira, Fernando | Olswold, Curtis | Slager, Susan | Pilarski, Robert | Ademuyiwa, Foluso | Konstantopoulou, Irene | Martin, Nicholas G | Montgomery, Grant W | Slamon, Dennis J | Rauh, Claudia | Lux, Michael P | Jud, Sebastian M | Bruning, Thomas | Weaver, Joellen | Sharma, Priyanka | Pathak, Harsh | Tapper, Will | Gerty, Sue | Durcan, Lorraine | Trichopoulos, Dimitrios | Tumino, Rosario | Peeters, Petra H | Kaaks, Rudolf | Campa, Daniele | Canzian, Federico | Weiderpass, Elisabete | Johansson, Mattias | Khaw, Kay-Tee | Travis, Ruth | Clavel-Chapelon, Françoise | Kolonel, Laurence N | Chen, Constance | Beck, Andy | Hankinson, Susan E | Berg, Christine D | Hoover, Robert N | Lissowska, Jolanta | Figueroa, Jonine D | Chasman, Daniel I | Gaudet, Mia M | Diver, W Ryan | Willett, Walter C | Hunter, David J | Simard, Jacques | Benitez, Javier | Dunning, Alison M | Sherman, Mark E | Chenevix-Trench, Georgia | Chanock, Stephen J | Hall, Per | Pharoah, Paul D P | Vachon, Celine | Easton, Douglas F | Haiman, Christopher A | Kraft, Peter
Nature genetics  2013;45(4):392-398e2.
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. 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.
doi:10.1038/ng.2561
PMCID: PMC3771695  PMID: 23535733
24.  Small RNAs in the peripheral blood discriminate metastasized from non-metastasized seminoma 
Molecular Cancer  2014;13:47.
Background
We aimed to better discriminate metastasized (lymphogen/occult/both combined) from non-metastasized seminoma based on post-transcriptional changes examined in the peripheral blood.
Methods
Total RNAs including small RNAs were isolated from the peripheral blood of patients suffering from metastasized testicular tumours (lymphogen, n = 5, clinical stage IIb/c; occult, n = 5, clinical stage I) and non-metastasized patients (n = 5, clinical stage I). Small RNA next generation sequencing (SOLID, Life Technologies) was employed to examine post-transcriptional changes. We searched for small RNAs showing at least 50 reads and a significant ≥ 2-fold difference using peripheral blood small RNAs of non-metastasized tumours as the reference group. Candidate small RNAs were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines.
Results
On average 1.3x107, 1.2x107 and 1.2x107 small RNA reads were detectable in non-metastasized, lymphogen and occult metastasized seminoma, respectively of which 73-76% remained after trimming. From these between 80-82% represented annotated reads and 7.2-7.8% (1.6-1.7x104) were annotated small RNA tags. Of them 137 small RNAs showed > 50 reads and a ≥ two-fold difference to the reference. In univariate analysis we detected 33-35 different small RNAs which significantly discriminated lymphogen/occult/combined metastasized from non-metastasized seminoma and among these different comparisons it were the same small RNAs in 44-79%. Many combinations of two of these small RNAs completely discriminated metastasized from non-metastasized seminoma irrespective of the metastasis subtype.
Conclusions
Metastasized (either lymphogen or occult) seminoma can be completely discriminated from non-metastasized seminoma with a combination of two small RNAs measured in the peripheral blood.
doi:10.1186/1476-4598-13-47
PMCID: PMC3975631  PMID: 24597607
Testis tumour; Gene expression; Small RNA; MicroRNA; Metastasized seminoma; Next generation sequencing; Risk factor; Tumour marker; Blood
25.  The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data 
Thompson, Paul M. | Stein, Jason L. | Medland, Sarah E. | Hibar, Derrek P. | Vasquez, Alejandro Arias | Renteria, Miguel E. | Toro, Roberto | Jahanshad, Neda | Schumann, Gunter | Franke, Barbara | Wright, Margaret J. | Martin, Nicholas G. | Agartz, Ingrid | Alda, Martin | Alhusaini, Saud | Almasy, Laura | Almeida, Jorge | Alpert, Kathryn | Andreasen, Nancy C. | Andreassen, Ole A. | Apostolova, Liana G. | Appel, Katja | Armstrong, Nicola J. | Aribisala, Benjamin | Bastin, Mark E. | Bauer, Michael | Bearden, Carrie E. | Bergmann, Ørjan | Binder, Elisabeth B. | Blangero, John | Bockholt, Henry J. | Bøen, Erlend | Bois, Catherine | Boomsma, Dorret I. | Booth, Tom | Bowman, Ian J. | Bralten, Janita | Brouwer, Rachel M. | Brunner, Han G. | Brohawn, David G. | Buckner, Randy L. | Buitelaar, Jan | Bulayeva, Kazima | Bustillo, Juan R. | Calhoun, Vince D. | Cannon, Dara M. | Cantor, Rita M. | Carless, Melanie A. | Caseras, Xavier | Cavalleri, Gianpiero L. | Chakravarty, M. Mallar | Chang, Kiki D. | Ching, Christopher R. K. | Christoforou, Andrea | Cichon, Sven | Clark, Vincent P. | Conrod, Patricia | Coppola, Giovanni | Crespo-Facorro, Benedicto | Curran, Joanne E. | Czisch, Michael | Deary, Ian J. | de Geus, Eco J. C. | den Braber, Anouk | Delvecchio, Giuseppe | Depondt, Chantal | de Haan, Lieuwe | de Zubicaray, Greig I. | Dima, Danai | Dimitrova, Rali | Djurovic, Srdjan | Dong, Hongwei | Donohoe, Gary | Duggirala, Ravindranath | Dyer, Thomas D. | Ehrlich, Stefan | Ekman, Carl Johan | Elvsåshagen, Torbjørn | Emsell, Louise | Erk, Susanne | Espeseth, Thomas | Fagerness, Jesen | Fears, Scott | Fedko, Iryna | Fernández, Guillén | Fisher, Simon E. | Foroud, Tatiana | Fox, Peter T. | Francks, Clyde | Frangou, Sophia | Frey, Eva Maria | Frodl, Thomas | Frouin, Vincent | Garavan, Hugh | Giddaluru, Sudheer | Glahn, David C. | Godlewska, Beata | Goldstein, Rita Z. | Gollub, Randy L. | Grabe, Hans J. | Grimm, Oliver | Gruber, Oliver | Guadalupe, Tulio | Gur, Raquel E. | Gur, Ruben C. | Göring, Harald H. H. | Hagenaars, Saskia | Hajek, Tomas | Hall, Geoffrey B. | Hall, Jeremy | Hardy, John | Hartman, Catharina A. | Hass, Johanna | Hatton, Sean N. | Haukvik, Unn K. | Hegenscheid, Katrin | Heinz, Andreas | Hickie, Ian B. | Ho, Beng-Choon | Hoehn, David | Hoekstra, Pieter J. | Hollinshead, Marisa | Holmes, Avram J. | Homuth, Georg | Hoogman, Martine | Hong, L. Elliot | Hosten, Norbert | Hottenga, Jouke-Jan | Hulshoff Pol, Hilleke E. | Hwang, Kristy S. | Jack, Clifford R. | Jenkinson, Mark | Johnston, Caroline | Jönsson, Erik G. | Kahn, René S. | Kasperaviciute, Dalia | Kelly, Sinead | Kim, Sungeun | Kochunov, Peter | Koenders, Laura | Krämer, Bernd | Kwok, John B. J. | Lagopoulos, Jim | Laje, Gonzalo | Landen, Mikael | Landman, Bennett A. | Lauriello, John | Lawrie, Stephen M. | Lee, Phil H. | Le Hellard, Stephanie | Lemaître, Herve | Leonardo, Cassandra D. | Li, Chiang-shan | Liberg, Benny | Liewald, David C. | Liu, Xinmin | Lopez, Lorna M. | Loth, Eva | Lourdusamy, Anbarasu | Luciano, Michelle | Macciardi, Fabio | Machielsen, Marise W. J. | MacQueen, Glenda M. | Malt, Ulrik F. | Mandl, René | Manoach, Dara S. | Martinot, Jean-Luc | Matarin, Mar | Mather, Karen A. | Mattheisen, Manuel | Mattingsdal, Morten | Meyer-Lindenberg, Andreas | McDonald, Colm | McIntosh, Andrew M. | McMahon, Francis J. | McMahon, Katie L. | Meisenzahl, Eva | Melle, Ingrid | Milaneschi, Yuri | Mohnke, Sebastian | Montgomery, Grant W. | Morris, Derek W. | Moses, Eric K. | Mueller, Bryon A. | Muñoz Maniega, Susana | Mühleisen, Thomas W. | Müller-Myhsok, Bertram | Mwangi, Benson | Nauck, Matthias | Nho, Kwangsik | Nichols, Thomas E. | Nilsson, Lars-Göran | Nugent, Allison C. | Nyberg, Lars | Olvera, Rene L. | Oosterlaan, Jaap | Ophoff, Roel A. | Pandolfo, Massimo | Papalampropoulou-Tsiridou, Melina | Papmeyer, Martina | Paus, Tomas | Pausova, Zdenka | Pearlson, Godfrey D. | Penninx, Brenda W. | Peterson, Charles P. | Pfennig, Andrea | Phillips, Mary | Pike, G. Bruce | Poline, Jean-Baptiste | Potkin, Steven G. | Pütz, Benno | Ramasamy, Adaikalavan | Rasmussen, Jerod | Rietschel, Marcella | Rijpkema, Mark | Risacher, Shannon L. | Roffman, Joshua L. | Roiz-Santiañez, Roberto | Romanczuk-Seiferth, Nina | Rose, Emma J. | Royle, Natalie A. | Rujescu, Dan | Ryten, Mina | Sachdev, Perminder S. | Salami, Alireza | Satterthwaite, Theodore D. | Savitz, Jonathan | Saykin, Andrew J. | Scanlon, Cathy | Schmaal, Lianne | Schnack, Hugo G. | Schork, Andrew J. | Schulz, S. Charles | Schür, Remmelt | Seidman, Larry | Shen, Li | Shoemaker, Jody M. | Simmons, Andrew | Sisodiya, Sanjay M. | Smith, Colin | Smoller, Jordan W. | Soares, Jair C. | Sponheim, Scott R. | Sprooten, Emma | Starr, John M. | Steen, Vidar M. | Strakowski, Stephen | Strike, Lachlan | Sussmann, Jessika | Sämann, Philipp G. | Teumer, Alexander | Toga, Arthur W. | Tordesillas-Gutierrez, Diana | Trabzuni, Daniah | Trost, Sarah | Turner, Jessica | Van den Heuvel, Martijn | van der Wee, Nic J. | van Eijk, Kristel | van Erp, Theo G. M. | van Haren, Neeltje E. M. | van ‘t Ent, Dennis | van Tol, Marie-Jose | Valdés Hernández, Maria C. | Veltman, Dick J. | Versace, Amelia | Völzke, Henry | Walker, Robert | Walter, Henrik | Wang, Lei | Wardlaw, Joanna M. | Weale, Michael E. | Weiner, Michael W. | Wen, Wei | Westlye, Lars T. | Whalley, Heather C. | Whelan, Christopher D. | White, Tonya | Winkler, Anderson M. | Wittfeld, Katharina | Woldehawariat, Girma | Wolf, Christiane | Zilles, David | Zwiers, Marcel P. | Thalamuthu, Anbupalam | Schofield, Peter R. | Freimer, Nelson B. | Lawrence, Natalia S. | Drevets, Wayne
Brain Imaging and Behavior  2014;8(2):153-182.
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
doi:10.1007/s11682-013-9269-5
PMCID: PMC4008818  PMID: 24399358
Genetics; MRI; GWAS; Consortium; Meta-analysis; Multi-site

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