Browsing by Subject "VARIANTS"

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  • Weiss, Alexander; Baselmans, Bart M. L.; Hofer, Edith; Yang, Jingyun; Okbay, Aysu; Lind, Penelope A.; Miller, Mike B.; Nolte, Ilja M.; Zhao, Wei; Hagenaars, Saskia P.; Hottenga, Jouke-Jan; Matteson, Lindsay K.; Snieder, Harold; Faul, Jessica D.; Hartman, Catharina A.; Boyle, Patricia A.; Tiemeier, Henning; Mosing, Miriam A.; Pattie, Alison; Davies, Gail; Liewald, David C.; Schmidt, Reinhold; De Jager, Philip L.; Heath, Andrew C.; Jokela, Markus; Starr, John M.; Oldehinkel, Albertine J.; Johannesson, Magnus; Cesarini, David; Hofman, Albert; Harris, Sarah E.; Smith, Jennifer A.; Keltikangas-Järvinen, Liisa; Pulkki-Råback, Laura; Schmidt, Helena; Smith, Jacqui; Iacono, William G.; McGue, Matt; Bennett, David A.; Pedersen, Nancy L.; Magnusson, Patrik K. E.; Deary, Ian J.; Martin, Nicholas G.; Boomsma, Dorret I.; Bartels, Meike; Luciano, Michelle (2016)
    Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes
  • Prokopenko, Inga; Poon, Wenny; Maegi, Reedik; Prasad, Rashmi B.; Salehi, S. Albert; Almgren, Peter; Osmark, Peter; Bouatia-Naji, Nabila; Wierup, Nils; Fall, Tove; Stancakova, Alena; Barker, Adam; Lagou, Vasiliki; Osmond, Clive; Xie, Weijia; Lahti, Jari; Jackson, Anne U.; Cheng, Yu-Ching; Liu, Jie; O'Connell, Jeffrey R.; Blomstedt, Paul A.; Fadista, Joao; Alkayyali, Sami; Dayeh, Tasnim; Ahlqvist, Emma; Taneera, Jalal; Lecoeur, Cecile; Kumar, Ashish; Hansson, Ola; Hansson, Karin; Voight, Benjamin F.; Kang, Hyun Min; Levy-Marchal, Claire; Vatin, Vincent; Palotie, Aarno; Syvanen, Ann-Christine; Mari, Andrea; Weedon, Michael N.; Loos, Ruth J. F.; Ong, Ken K.; Nilsson, Peter; Isomaa, Bo; Tuomi, Tiinamaija; Wareham, Nicholas J.; Stumvoll, Michael; Widen, Elisabeth; Lakka, Timo A.; Langenberg, Claudia; Tonjes, Anke; Rauramaa, Rainer; Kuusisto, Johanna; Frayling, Timothy M.; Froguel, Philippe; Walker, Mark; Eriksson, Johan G.; Ling, Charlotte; Kovacs, Peter; Ingelsson, Erik; McCarthy, Mark I.; Shuldiner, Alan R.; Silver, Kristi D.; Laakso, Markku; Groop, Leif; Lyssenko, Valeriya (2014)
  • Frischknecht, Mirjam; Niehof-Oellers, Helena; Jagannathan, Vidhya; Owczarek-Lipska, Marta; Droegemueller, Cord; Dietschi, Elisabeth; Dolf, Gaudenz; Tellhelm, Bernd; Lang, Johann; Tiira, Katriina; Lohi, Hannes; Leeb, Tosso (2013)
  • Thorgeirsson, T. E.; Gudbjartsson, D. F.; Sulem, P.; Besenbacher, S.; Styrkarsdottir, U.; Thorleifsson, G.; Walters, G. B.; Furberg, H.; Sullivan, P. F.; Marchini, J.; McCarthy, M. I.; Steinthorsdottir, V.; Thorsteinsdottir, U.; Stefansson, K.; TAG Consortium; Oxford-GSK Consortium; ENGAGE Consortium; Kaprio, Jaakko; Tuomilehto, Jaakko; Shen, Huei-Yi (2013)
  • Li, Dong; Chang, Xiao; Connolly, John J.; Tian, Lifeng; Liu, Yichuan; Bhoj, Elizabeth J.; Robinson, Nora; Abrams, Debra; Li, Yun R.; Bradfield, Jonathan P.; Kim, Cecilia E.; Li, Jin; Wang, Fengxiang; Snyder, James; Lemma, Maria; Hou, Cuiping; Wei, Zhi; Guo, Yiran; Qiu, Haijun; Mentch, Frank D.; Thomas, Kelly A.; Chiavacci, Rosetta M.; Cone, Roger; Li, Bingshan; Sleiman, Patrick A.; Hakonarson, Hakon; Eating Disorders Working Group of the Psychiatric Genomics Consortium; Kaprio, Jaakko; Palotie, Aarno; Raevuori-Helkamaa, Anu; Ripatti, Samuli; Price Fdn Collaborative Grp (2017)
    We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 x 10(-7); OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.
  • Service, S. K.; Verweij, K. J. H.; Lahti, J.; Congdon, E.; Ekelund, J.; Hintsanen, M.; Räikkönen, Katri; Lehtimaki, T.; Kahonen, M.; Widen, E.; Taanila, A.; Veijola, J.; Heath, A. C.; Madden, P. A. F.; Montgomery, G. W.; Sabatti, C.; Jarvelin, M-R; Palotie, A.; Raitakari, O.; Viikari, J.; Martin, N. G.; Eriksson, J. G.; Keltikangas-Järvinen, Liisa; Wray, N. R.; Freimer, N. B. (2012)
  • Bodea, Corneliu A.; Neale, Benjamin M.; Ripke, Stephan; Daly, Mark J.; Devlin, Bernie; Roeder, Kathryn; Int IBD Genetics Consortium; Palotie, A. (2016)
    One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.
  • Escala-Garcia, M.; Abraham, J.; Andrulis, I.L.; Anton-Culver, H.; Arndt, V.; Ashworth, A.; Auer, P.L.; Auvinen, P.; Beckmann, M.W.; Beesley, J.; Behrens, S.; Benitez, J.; Bermisheva, M.; Blomqvist, C.; Blot, W.; Bogdanova, N.V.; Bojesen, S.E.; Bolla, M.K.; Børresen-Dale, A.-L.; Brauch, H.; Brenner, H.; Brucker, S.Y.; Burwinkel, B.; Caldas, C.; Canzian, F.; Chang-Claude, J.; Chanock, S.J.; Chin, S.-F.; Clarke, C.L.; Couch, F.J.; Cox, A.; Cross, S.S.; Czene, K.; Daly, M.B.; Dennis, J.; Devilee, P.; Dunn, J.A.; Dunning, A.M.; Dwek, M.; Earl, H.M.; Eccles, D.M.; Eliassen, A.H.; Ellberg, C.; Evans, D.G.; Fasching, P.A.; Figueroa, J.; Flyger, H.; Gago-Dominguez, M.; Gapstur, S.M.; García-Closas, M.; García-Sáenz, J.A.; Gaudet, M.M.; George, A.; Giles, G.G.; Goldgar, D.E.; González-Neira, A.; Grip, M.; Guénel, P.; Guo, Q.; Haiman, C.A.; Håkansson, N.; Hamann, U.; Harrington, P.A.; Hiller, L.; Hooning, M.J.; Hopper, J.L.; Howell, A.; Huang, C.-S.; Huang, G.; Hunter, D.J.; Jakubowska, A.; John, E.M.; Kaaks, R.; Kapoor, P.M.; Keeman, R.; Kitahara, C.M.; Koppert, L.B.; Kraft, P.; Kristensen, V.N.; Lambrechts, D.; Le Marchand, L.; Lejbkowicz, F.; Lindblom, A.; Lubiński, J.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martinez, M.E.; Maurer, T.; Mavroudis, D.; Meindl, A.; Milne, R.L.; Mulligan, A.M.; Neuhausen, S.L.; Nevanlinna, H.; Newman, W.G.; Olshan, A.F.; Olson, J.E.; Olsson, H.; Orr, N.; Peterlongo, P.; Petridis, C.; Prentice, R.L.; Presneau, N.; Punie, K.; Ramachandran, D.; Rennert, G.; Romero, A.; Sachchithananthan, M.; Saloustros, E.; Sawyer, E.J.; Schmutzler, R.K.; Schwentner, L.; Scott, C.; Simard, J.; Sohn, C.; Southey, M.C.; Swerdlow, A.J.; Tamimi, R.M.; Tapper, W.J.; Teixeira, M.R.; Terry, M.B.; Thorne, H.; Tollenaar, R.A.E.M.; Tomlinson, I.; Troester, M.A.; Truong, T.; Turnbull, C.; Vachon, C.M.; van der Kolk, L.E.; Wang, Q.; Winqvist, R.; Wolk, A.; Yang, X.R.; Ziogas, A.; Pharoah, P.D.P.; Hall, P.; Wessels, L.F.A.; Chenevix-Trench, G.; Bader, G.D.; Dörk, T.; Easton, D.F.; Canisius, S.; Schmidt, M.K. (2020)
    Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
  • Genome Aggregation Database Prod T; Genome Aggregation Database Consor; Collins, Ryan L.; Brand, Harrison; Karczewski, Konrad J.; Talkowski, Michael E.; Färkkilä, Martti; Groop, Leif; Holi, Matti M.; Kaprio, Jaakko; Palotie, Aarno; Ripatti, Samuli; Tuomi, Tiinamaija; Wessman, Maija; Kallela, Mikko (2020)
    Structural variants (SVs) rearrange large segments of DNA(1) and can have profound consequences in evolution and human disease(2,3). As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)(4) have become integral in the interpretation of single-nucleotide variants (SNVs)(5). However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage(6). We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings(7). This SV resource is freely distributed via the gnomAD browser(8) and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
  • Early Growth Genetics Consortium; Bradfield, Jonathan P.; Vogelezang, Suzanne; Pitkänen, Niina; Leinonen, Jaakko T.; Lindi, Virpi; Atalay, Mustafa; Kähönen, Mika; Raitakari, Olli T.; Eriksson, Johan; Widen, Elisabeth (2019)
    Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13005 cases (>= 95th percentile of body mass index (BMI) achieved 2-18 years old) and 15599 controls (consistently
  • Carlsson, Annelie; Shepherd, Maggie; Ellard, Sian; Weedon, Michael; Lernmark, Ake; Forsander, Gun; Colclough, Kevin; Brahimi, Qefsere; Valtonen-Andre, Camilla; Ivarsson, Sten A.; Elding Larsson, Helena; Samuelsson, Ulf; Ortqvist, Eva; Groop, Leif; Ludvigsson, Johnny; Marcus, Claude; Hattersley, Andrew T. (2020)
    OBJECTIVE Identifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population. RESEARCH DESIGN AND METHODS Swedish patients (n = 3,933) aged 1-18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing. RESULTS The minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 x 10(-44)), HbA(1c) (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 x 10(-20)), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 x 10(-19)), parental diabetes (63% vs. 12%; P = 1 x 10(-15)), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA(1c)
  • PanScan PanC4 consortia; Walsh, Naomi; Zhang, Han; Männistö, Satu; Weiderpass, Elisabete (2019)
    Background Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P Conclusion Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
  • Batcha, Aarif M. N.; Bamopoulos, Stefanos A.; Kerbs, Paul; Kumar, Ashwini; Jurinovic, Vindi; Rothenberg-Thurley, Maja; Ksienzyk, Bianka; Philippou-Massier, Julia; Krebs, Stefan; Blum, Helmut; Schneider, Stephanie; Konstandin, Nikola; Bohlander, Stefan K.; Heckman, Caroline; Kontro, Mika; Hiddemann, Wolfgang; Spiekermann, Karsten; Braess, Jan; Metzeler, Klaus H.; Greif, Philipp A.; Mansmann, Ulrich; Herold, Tobias (2019)
    The patho-mechanism of somatic driver mutations in cancer usually involves transcription, but the proportion of mutations and wild-type alleles transcribed from DNA to RNA is largely unknown. We systematically compared the variant allele frequencies of recurrently mutated genes in DNA and RNA sequencing data of 246 acute myeloid leukaemia (AML) patients. We observed that 95% of all detected variants were transcribed while the rest were not detectable in RNA sequencing with a minimum read-depth cut-off (10x). Our analysis focusing on 11 genes harbouring recurring mutations demonstrated allelic imbalance (AI) in most patients. GATA2, RUNX1, TET2, SRSF2, IDH2, PTPN11, WT1, NPM1 and CEBPA showed significant AIs. While the effect size was small in general, GATA2 exhibited the largest allelic imbalance. By pooling heterogeneous data from three independent AML cohorts with paired DNA and RNA sequencing (N = 253), we could validate the preferential transcription of GATA2-mutated alleles. Differential expression analysis of the genes with significant AI showed no significant differential gene and isoform expression for the mutated genes, between mutated and wild-type patients. In conclusion, our analyses identified AI in nine out of eleven recurrently mutated genes. AI might be a common phenomenon in AML which potentially contributes to leukaemogenesis.
  • Japan Scoliosis Clinical Res Grp; Texas Scottish Rite Hosp Children (2018)
    Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 x 10(-18) (odds ratio = 1.19, 95% confidence interval = 1.14-1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.
  • Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Neuhausen, Susan L.; Ding, Yuan Chun; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C.; Hansen, Thomas V. O.; Osorio, Ana; Benitez, Javier; Andres Conejero, Raquel; Segota, Ena; Weitzel, Jeffrey N.; Thelander, Margo; Peterlongo, Paolo; Radice, Paolo; Pensotti, Valeria; Dolcetti, Riccardo; Bonanni, Bernardo; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Manoukian, Siranoush; Varesco, Liliana; Capone, Gabriele L.; Papi, Laura; Ottini, Laura; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brady, Angela; Brewer, Carole; Foo, Claire; Evans, D. Gareth; Frost, Debra; Eccles, Diana; Douglas, Fiona; Cook, Jackie; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Tischkowitz, Marc; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Cole, Trevor; Godwin, Andrew K.; Isaacs, Claudine; Claes, Kathleen; De Leeneer, Kim; Meindl, Alfons; Gehrig, Andrea; Wappenschmidt, Barbara; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Schmutzler, Rita K.; Preisler-Adams, Sabine; Markov, Nadja Bogdanova; Wang-Gohrke, Shan; de Pauw, Antoine; Lefol, Cedrick; Lasset, Christine; Leroux, Dominique; Rouleau, Etienne; Damiola, Francesca; Dreyfus, Helene; Barjhoux, Laure; Golmard, Lisa; Uhrhammer, Nancy; Bonadona, Valerie; Sornin, Valerie; Bignon, Yves-Jean; Carter, Jonathan; Van Le, Linda; Piedmonte, Marion; DiSilvestro, Paul A.; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Aittomaki, Kristiina; Jager, Agnes; van den Ouweland, Ans M. W.; Kets, Carolien M.; Aalfs, Cora M.; van Leeuwen, Flora E.; Hogervorst, Frans B. L.; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Roozendaal, Kees E. P.; Rookus, Matti A.; Devilee, Peter; van der Luijt, Rob B.; Olah, Edith; Diez, Orland; Teule, Alex; Lazaro, Conxi; Blanco, Ignacio; Del Valle, Jesus; Jakubowska, Anna; Sukiennicki, Grzegorz; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Agnarsson, Bjarni A.; Maugard, Christine; Amadori, Alberto; Montagna, Marco; Teixeira, Manuel R.; Spurdle, Amanda B.; Foulkes, William; Olswold, Curtis; Lindor, Noralane M.; Pankratz, Vernon S.; Szabo, Csilla I.; Lincoln, Anne; Jacobs, Lauren; Corines, Marina; Robson, Mark; Vijai, Joseph; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Imyanitov, Evgeny N.; Mulligan, Anna Marie; Glendon, Gord; Andrulis, Irene L.; Tchatchou, Sandrine; Toland, Amanda Ewart; Pedersen, Inge Sokilde; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Caligo, Maria A.; Friedman, Eitan; Zidan, Jamal; Laitman, Yael; Lindblom, Annika; Melin, Beatrice; Arver, Brita; Loman, Niklas; Rosenquist, Richard; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Ramus, Susan J.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Mitchell, Gillian; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Stoppa-Lyonnet, Dominique; Thomas, Gilles; Simard, Jacques; Couch, Fergus J.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Mazoyer, Sylvie; Phelan, Catherine M.; Sinilnikova, Olga M.; Cox, David G.; Breast Canc Family Registry; EMBRACE; GEMO Study Collaborators; HEBON (2015)
    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
  • Lokki, A. Inkeri; Kaartokallio, Tea; Holmberg, Ville; Onkamo, Paivi; Koskinen, Lotta L. E.; Saavalainen, Paivi; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Villa, Pia M.; Hiltunen, Leena; Laivuori, Hannele; Meri, Seppo (2017)
    Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.
  • Rees, E.; Kirov, G.; Walters, J. T.; Richards, A. L.; Howrigan, D.; Kavanagh, D. H.; Pocklington, A. J.; Fromer, M.; Ruderfer, D. M.; Georgieva, L.; Carrera, N.; Gormley, P.; Palta, P.; Williams, H.; Dwyer, S.; Johnson, J. S.; Roussos, P.; Barker, D. D.; Banks, E.; Milanova, V.; Rose, S. A.; Chambert, K.; Mahajan, M.; Scolnick, E. M.; Moran, J. L.; Tsuang, M. T.; Glatt, S. J.; Chen, W. J.; Hwu, H-G; Neale, B. M.; Palotie, A.; Sklar, P.; Purcell, S. M.; McCarroll, S. A.; Holmans, P.; Owen, M. J.; O'Donovan, M. C.; Taiwanese Trios Exome Sequencing C (2015)
    Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF
  • Siltanen, Sanna; Fischer, Daniel; Rantapero, Tommi; Laitinen, Virpi; Mpindi, John Patrick; Kallioniemi, Olli; Wahlfors, Tiina; Schleutker, Johanna (2013)
  • Leinonen, Jaakko T.; Surakka, Ida; Havulinna, Aki S.; Kettunen, Johannes; Luoto, Riitta; Salomaa, Veikko; Widen, Elisabeth (2012)
  • Fuertes, Elaine; Soderhall, Cilla; Acevedo, Nathalie; Becker, Allan; Brauer, Michael; Chan-Yeung, Moira; Dijk, F. Nicole; Heinrich, Joachim; de Jongste, Johan; Koppelman, Gerard H.; Postma, Dirkje S.; Kere, Juha; Kozyrskyj, Anita L.; Pershagen, Goran; Sandford, Andrew; Standl, Marie; Tiesler, Carla M. T.; Waldenberger, Melanie; Westman, Marit; Carlsten, Christopher; Melen, Erik (2015)