Browsing by Subject "LOCUS"

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  • 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)
  • Khrunin, Andrey V.; Khokhrin, Denis V.; Filippova, Irina N.; Esko, Tonu; Nelis, Mari; Bebyakova, Natalia A.; Bolotova, Natalia L.; Klovins, Janis; Nikitina-Zake, Liene; Rehnström, Karola Hannele; Ripatti, Samuli; Schreiber, Stefan; Franke, Andre; Macek, Milan; Krulisova, Veronika; Lubinski, Jan; Metspalu, Andres; Limborska, Svetlana A. (2013)
  • Arora, Geeti P.; Almgren, Peter; Brons, Charlotte; Thaman, Richa G.; Vaag, Allan A.; Groop, Leif; Prasad, Rashmi B. (2018)
    Background: Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Methods: Five thousand one hundred pregnant women of gestational age 24-28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. Results: In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p <0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. Conclusions: GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.
  • Lahti, Päivi; Lindström, Miia; Somervuo, Panu; Heikinheimo, Annamari; Korkeala, Hannu (2012)
    Clostridium perfringens, one of the most common causes of food poisonings, can carry the enterotoxin gene, cpe, in its chromosome or on a plasmid. C. perfringens food poisonings are more frequently caused by the chromosomal cpe-carrying strains, while the plasmid-borne cpe-positive genotypes are more commonly found in the human feces and environmental samples. Different tolerance to food processing conditions by the plasmid-borne and chromosomal cpe-carrying strains has been reported, but the reservoirs and contamination routes of enterotoxin-producing C. perfringens remain unknown. A comparative genomic hybridization (CGH) analysis with a DNA microarray based on three C. perfringens type A genomes was conducted to shed light on the epidemiology of C. perfringens food poisonings caused by plasmid-borne and chromosomal cpe-carrying strains by comparing chromosomal and plasmid-borne cpe-positive and cpe-negative C. perfringens isolates from human, animal, environmental, and food samples. The chromosomal and plasmid-borne cpe-positive C. perfringens genotypes formed two distinct clusters. Variable genes were involved with myo-inositol, ethanolamine and cellobiose metabolism, suggesting a new epidemiological model for C. perfringens food poisonings. The CGH results were complemented with growth studies, which demonstrated different myo-inositol, ethanolamine, and cellobiose metabolism between the chromosomal and plasmid-borne cpe-carrying strains. These findings support a ubiquitous occurrence of the plasmid-borne cpe-positive strains and their adaptation to the mammalian intestine, whereas the chromosomal cpe-positive strains appear to have a narrow niche in environments containing degrading plant material. Thus the epidemiology of the food poisonings caused by two populations appears different, the plasmid-borne cpe-positive strains probably contaminating foods via humans and the chromosomal strains being connected to plant material.
  • Marjonen, Heidi; Toivonen, Mia; Lahti, Laura; Kaminen-Ahola, Nina (2018)
    Prenatal alcohol exposure (PAE) can harm the embryonic development and cause life-long consequences in offspring's health. To clarify the molecular mechanisms of PAE we have used a mouse model of early alcohol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first eight days of gestation (GD 0.5-8.5). Owing to the detected postnatal growth-restricted phenotype in the offspring of this mouse model and both prenatal and postnatal growth restriction in alcohol-exposed humans, we focused on imprinted genes Insulin-like growth factor 2 (Igf2), H19, Small Nuclear Ribonucleoprotein Polypeptide N (Snrpn) and Paternally expressed gene 3 (Peg3), which all are known to be involved in embryonic and placental growth and development. We studied the effects of alcohol on DNA methylation level at the Igf2/H19 imprinting control region (ICR), Igf2 differentially methylated region 1, Snrpn ICR and Peg3 ICR in 9.5 embryonic days old (E9.5) embryos and placentas by using MassARRAY EpiTYPER. To determine alcohol-induced alterations globally, we also examined methylation in long interspersed nuclear elements (Line-1) in E9.5 placentas. We did not observe any significant alcohol-induced changes in DNA methylation levels. We explored effects of PAE on gene expression of E9.5 embryos as well as E9.5 and E16.5 placentas by using quantitative PCR. The expression of growth promoter gene Igf2 was decreased in the alcohol-exposed E9.5 and E16.5 placentas. The expression of negative growth controller H19 was significantly increased in the alcohol exposed E9.5 embryos compared to controls, and conversely, a trend of decreased expression in alcohol-exposed E9.5 and E16.5 placentas were observed. Furthermore, increased Snrpn expression in alcohol-exposed E9.5 embryos was also detected. Our study indicates that albeit no alterations in the DNA methylation levels of studied sequences were detected by EpiTYPER, early PAE can affect the expression of imprinted genes in both developing embryo and placenta.
  • Ghoussaini, Maya; French, Juliet D.; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mandi Moradi; Lee, Jason S.; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Milne, Roger L.; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guenel, Pascal; Truong, Therese; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; Gonzalez-Neira, Anna; Alonso, Rosario; Pita, Guillermo; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C.; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; kConFab AOCS; NBCS Collaborators (2016)
    Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,49545,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 x 10(-3)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 x 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 x 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in similar to 10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
  • Hällfors, Jenni; Palviainen, Teemu; Surakka, Ida; Gupta, Richa; Buchwald, Jadwiga; Raevuori, Anu; Ripatti, Samuli; Korhonen, Tellervo; Jousilahti, Pekka; Madden, Pamela A. F.; Kaprio, Jaakko; Loukola, Anu (2019)
    The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 x 10(-9)), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-kappa B transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 x 10(-9)), and on 11p15 (P = 6.6 x 10(-8)) in an intron of AP2A2, and P = 4.2 x 10(-7) for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 x 10(-8)) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.
  • Salminen, Tiina S.; Cannino, Giuseppe; Oliveira, Marcos T.; Lillsunde, Päivi; Jacobs, Howard T.; Kaguni, Laurie S. (2019)
    Drosophila melanogaster, like most animal species, displays considerable genetic variation in both nuclear and mitochondrial DNA (mtDNA). Here we tested whether any of four natural mtDNA variants was able to modify the effect of the phenotypically mild, nuclear tko(25t) mutation, affecting mitochondrial protein synthesis. When combined with tko(25t), the mtDNA from wild strain KSA2 produced pupal lethality, accompanied by the presence of melanotic nodules in L3 larvae. KSA2 mtDNA, which carries a substitution at a conserved residue of cytochrome b that is predicted to be involved in subunit interactions within respiratory complex III, conferred drastically decreased respiratory capacity and complex III activity in the tko(25t) but not a wild-type nuclear background. The complex III inhibitor antimycin A was able to phenocopy effects of the tko(25t) mutation in the KSA2 mtDNA background. This is the first report of a lethal, nuclear-mitochondrial interaction within a metazoan species, representing a paradigm for understanding genetic interactions between nuclear and mitochondrial genotype relevant to human health and disease.
  • Arora, G. P.; Åkerlund, M.; Brons, C.; Moen, G-H; Wasenius, N. S.; Sommer, C.; Jenum, A. K.; Almgren, P.; Thaman, R. G.; Orho-Melander, M.; Eriksson, J.; Qvigstad, E.; Birkeland, K.; Berntorp, K.; Vaag, A. A.; Groop, L.; Prasad, R. B. (2019)
    Objective Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. Methods Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). Results Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. Conclusions Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.
  • Udden, Fabian; Filipe, Matuba; Slotved, Hans-Christian; Yamba-Yamba, Linda; Fuursted, Kurt; Kuatoko, Palmira Pintar; Larsson, Mans; Bjurgert, Jonas; Mansson, Viktor; Pelkonen, Tuula; Reimer, Ake; Riesbeck, Kristian (2020)
    Children in Angola are affected by a high burden of disease caused by pneumococcal infections. The 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the childhood immunization programme in 2013 but the serotype distribution of Streptococcus pneumoniae and antimicrobial susceptibility patterns are unknown. We did a cross-sectional nasopharyngeal carriage study in Luanda and Saurimo, Angola (PCV13 3rd dose coverage 67% and 84%, respectively) during November to December 2017 comprising 940 children aged 4-12 years. The main objective was to assess vaccine serotype coverage and antimicrobial susceptibility rates for S. pneumoniae. Our secondary aim was to characterize colonizinig strains of Haemophilus influenzae and Moraxella catarrhalis. Pneumococcal colonization was found in 35% (95% CI 32-39%) of children (n = 332), with 41% of serotypes covered by PCV13. The most common serotypes were 3 (8%), 18C (6%), 23F (6%), 11A (6%), 34 (6%), 19F (5%) and 16 (5%). Carriage of H. influenzae and M. catarrhalis was detected in 13% (95% CI 11-15%) and 15% (95% CI 13-17%) of children, respectively. Non-susceptibility to penicillin was common among pneumococci (40%), particularly among PCV13-included serotypes (50% vs. 33%; p = 0.003), although the median minimal inhibitory concentration was low (0.19 mg/mL, IQR 0.13-0.25 mg/mL). Most pneumococci and H. influenzae were susceptible to amoxicillin (99% and 88%, respectively). Furthermore, resistance to trimethoprim-sulfamethoxazole was>70% among all three species. Multidrug-resistant pneumococci (non-susceptible to > 3 antibiotics; 7% [n = 24]) were further studied with whole genome sequencing to investigate clonality as an underlying cause for this phenotype. No clearly dominating clone(s) were, however, detected. The results indicate that continued use of PCV13 may have positive direct and herd effects on pneumococcal infections in Angola as carriage of vaccine serotypes was common in the non-vaccinated age group. Finally, amoxicillin is assessed to be a feasible empirical treatment of respiratory tract infections in Angola. (C) 2020 The Author(s). Published by Elsevier Ltd.
  • Mavaddat, Nasim; Michailidou, Kyriaki; Dennis, Joe; Lush, Michael; Fachal, Laura; Lee, Andrew; Tyrer, Jonathan P.; Chen, Ting-Huei; Wang, Qin; Bolla, Manjeet K.; Yang, Xin; Adank, Muriel A.; Ahearn, Thomas; Aittomäki, Kristiina; Allen, Jamie; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Auvinen, Päivi; Barrdahl, Myrto; Beane Freeman, Laura E.; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Bremer, Michael; Brenner, Hermann; Brentnall, Adam; Brock, Ian W.; Brooks-Wilson, Angela; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Campa, Daniele; Carter, Brian D.; Castelao, Jose E.; Chanock, Stephen J.; Chlebowski, Rowan; Christiansen, Hans; Clarke, Christine L.; Collée, J. Margriet; Cordina-Duverger, Emilie; Cornelissen, Sten; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Försti, Asta; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Georgoulias, Vassilios; Giles, Graham G.; Gilyazova, Irina R.; Glendon, Gord; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Grenaker Alnæs, Grethe I.; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hankinson, Susan E.; Harkness, Elaine F.; Hart, Steven N.; He, Wei; Hein, Alexander; Heyworth, Jane; Hillemanns, Peter; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Jakimovska, Milena; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Michael E.; Jukkola-Vuorinen, Arja; Jung, Audrey; Kaaks, Rudolf; Kaczmarek, Katarzyna; Kataja, Vesa; Keeman, Renske; Kerin, Michael J.; Khusnutdinova, Elza; Kiiski, Johanna I.; Knight, Julia A.; Ko, Yon-Dschun; Kosma, Veli-Matti; Koutros, Stella; Kristensen, Vessela N.; Krüger, Ute; Kühl, Tabea; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lejbkowicz, Flavio; Lilyquist, Jenna; Lindblom, Annika; Lindström, Sara; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lubiński, Jan; Lux, Michael P.; MacInnis, Robert J.; Maishman, Tom; Makalic, Enes; Maleva Kostovska, Ivana; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Martens, John W.M.; Martinez, Maria Elena; Mavroudis, Dimitrios; McLean, Catriona; Meindl, Alfons; Menon, Usha; Middha, Pooja; Miller, Nicola; Moreno, Fernando; Mulligan, Anna Marie; Mulot, Claire; Muñoz-Garzon, Victor M.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Newman, William G.; Nielsen, Sune F.; Nordestgaard, Børge G.; Norman, Aaron; Offit, Kenneth; Olson, Janet E.; Olsson, Håkan; Orr, Nick; Pankratz, V. Shane; Park-Simon, Tjoung-Won; Perez, Jose I.A.; Pérez-Barrios, Clara; Peterlongo, Paolo; Peto, Julian; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Polley, Eric C.; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Purrington, Kristen; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rau-Murthy, Rohini; Rennert, Gad; Rennert, Hedy S.; Rhenius, Valerie; Robson, Mark; Romero, Atocha; Ruddy, Kathryn J.; Ruebner, Matthias; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J.; Seynaeve, Caroline; Shah, Mitul; Sherman, Mark E.; Shrubsole, Martha J.; Shu, Xiao-Ou; Slager, Susan; Smeets, Ann; Sohn, Christof; Soucy, Penny; Southey, Melissa C.; Spinelli, John J.; Stegmaier, Christa; Stone, Jennifer; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Terry, Mary Beth; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Truong, Thérèse; Tzardi, Maria; Ulmer, Hans-Ulrich; Untch, Michael; Vachon, Celine M.; van Veen, Elke M.; Vijai, Joseph; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Zhang, Yan; Zheng, Wei; Ziogas, Argyrios; Dunning, Alison M.; Thompson, Deborah J.; Chenevix-Trench, Georgia; Chang-Claude, Jenny; Schmidt, Marjanka K.; Hall, Per; Milne, Roger L.; Pharoah, Paul D.P.; Antoniou, Antonis C.; Chatterjee, Nilanjan; Kraft, Peter; García-Closas, Montserrat; Simard, Jacques; Easton, Douglas F. (2019)
    Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
  • Neville, Matt J.; Wittemans, Laura B. L.; Pinnick, Katherine E.; Todorcevic, Marijana; Kaksonen, Risto; Pietiläinen, Kirsi H.; Luan, Jian'an; Scott, Robert A.; Wareham, Nicholas J.; Langenberg, Claudia; Karpe, Fredrik (2019)
    Waist-to-hip ratio (WHR) is a prominent cardiometabolic risk factor that increases cardio-metabolic disease risk independently of BMI and for which multiple genetic loci have been identified. However, WHR is a relatively crude proxy for fat distribution and it does not capture all variation in fat distribution. We here present a study of the role of coding genetic variants on fat mass in 6 distinct regions of the body, based on dual-energy X-ray absorptiometry imaging on more than 17k participants. We find that the missense variant CCDC92(S70C), previously associated with WHR, is associated specifically increased leg fat mass and reduced visceral but not subcutaneous central fat. The minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue samples. In addition, we identify two coding variants in SPATA20 and UQCC1 that are associated with arm fat mass. SPATA20(K422R) is a low-frequency variant with a large effect on arm fat only, and UQCC1(R51Q) is a common variant reaching significance for arm but showing similar trends in other subcutaneous fat depots. Our findings support the notion that different fat compartments are regulated by distinct genetic factors.
  • Pöntinen, Anna; Lindström, Miia; Skurnik, Mikael; Korkeala, Hannu (2017)
    To study the role of each two-component system (TCS) histidine kinase (HK) in stress tolerance of Listeria monocytogenes EGD-e, we monitored the growth of individual HIC deletion mutant strains under heat (42.5 degrees C), acid (pH 5.6), alkali (pH 9.4), osmotic (6% NaCl), ethanol (3.5 vol%), and oxidative (5 mM H2O2) stresses. The growth of Delta liaS (Delta lmo1021) strain was impaired under each stress, with the most notable decrease under heat and osmotic stresses. The Delta ivirS (Delta lmo1741) strain showed nearly completely restricted growth at high temperature and impaired growth in ethanol. The growth of Delta agrC (Delta lmo0050) strain was impaired under osmotic stress and slightly under oxidative stress. We successfully complemented the HIC mutations using a novel allelic exchange based approach. This approach avoided the copy-number problems associated with in trans complementation from a plasmid. The mutant phenotypes were restored to the wild-type level in the complemented strains. This study reveals novel knowledge on the HKs needed for growth of L monocytogenes EGD-e under abovementioned stress conditions, with LiaS playing multiple roles in stress tolerance of L monocytogenes EGD-e. (C) 2017 Elsevier Ltd. All rights reserved.
  • Taylor, Amy E.; Morris, Richard W.; Fluharty, Meg E.; Bjorngaard, Johan H.; Asvold, Bjorn Olav; Gabrielsen, Maiken E.; Campbell, Archie; Marioni, Riccardo; Kumari, Meena; Hallfors, Jenni; Mannisto, Satu; Marques-Vidal, Pedro; Kaakinen, Marika; Cavadino, Alana; Postmus, Iris; Husemoen, Lise Lotte N.; Skaaby, Tea; Ahluwalia, Tarunveer S.; Treur, Jorien L.; Willemsen, Gonneke; Dale, Caroline; Wannamethee, S. Goya; Lahti, Jari; Palotie, Aarno; Räikkönen, Katri; Kisialiou, Aliaksei; McConnachie, Alex; Padmanabhan, Sandosh; Wong, Andrew; Dalgard, Christine; Paternoster, Lavinia; Ben-Shlomo, Yoav; Tyrrell, Jessica; Horwood, John; Fergusson, David M.; Kennedy, Martin A.; Frayling, Tim; Nohr, Ellen A.; Christiansen, Lene; Kyvik, Kirsten Ohm; Kuh, Diana; Watt, Graham; Eriksson, Johan; Whincup, Peter H.; Vink, Jacqueline M.; Boomsma, Dorret I.; Smith, George Davey; Lawlor, Debbie; Linneberg, Allan; Ford, Ian; Jukema, J. Wouter; Power, Christine; Hypponen, Elina; Jarvelin, Marjo-Riitta; Preisig, Martin; Borodulin, Katja; Kaprio, Jaakko; Kivimaki, Mika; Smith, Blair H.; Hayward, Caroline; Romundstad, Pal R.; Sorensen, Thorkild I. A.; Munafo, Marcus R.; Sattar, Naveed (2014)
  • Vanhanen, Reetta; Heikkila, Nelli; Aggarwal, Kunal; Hamm, David; Tarkkila, Heikki; Pätilä, Tommi; Jokiranta, T. Sakari; Saramaki, Jari; Arstila, T. Petteri (2016)
    A diverse T cell receptor (TCR) repertoire is essential for adaptive immune responses and is generated by somatic recombination of TCR alpha and TCR beta gene segments in the thymus. Previous estimates of the total TCR diversity have studied the circulating mature repertoire, identifying 1 to 3 x 10(6) unique TCR beta and 0.5 x 10(6) TCR alpha sequences. Here we provide the first estimate of the total TCR diversity generated in the human thymus, an organ which in principle can be sampled in its entirety. High-throughput sequencing of samples from four pediatric donors detected up to 10.3 x 10(6) unique TCR beta sequences and 3.7 x 10(6) TCR alpha sequences, the highest directly observed diversity so far for either chain. To obtain an estimate of the total diversity we then used three different estimators, preseq and DivE, which measure the saturation of rarefaction curves, and Chao2, which measures the size of the overlap between samples. Our results provide an estimate of a thymic repertoire consisting of 40 to 70 x 10(6) unique TCR beta sequences and 60 to 100 x 10(6) TCR alpha sequences. The thymic repertoire is thus extremely diverse. Moreover, extrapolation of the data and comparison with earlier estimates of peripheral diversity also suggest that the thymic repertoire is transient, with different clones produced at different times. (C) 2016 Elsevier Ltd. All rights reserved.
  • Tamaki, Takayuki; Oya, Satoyo; Naito, Makiko; Ozawa, Yasuko; Furuya, Tomoyuki; Saito, Masato; Sato, Mayuko; Wakazaki, Mayumi; Toyooka, Kiminori; Fukuda, Hiroo; Helariutta, Ykä; Kondo, Yuki (2020)
    The phloem transports photosynthetic assimilates and signalling molecules. It mainly consists of sieve elements (SEs), which act as "highways" for transport, and companion cells (CCs), which serve as "gates" to load/unload cargos. Though SEs and CCs function together, it remains unknown what determines the ratio of SE/CC in the phloem. Here we develop a new culture system for CC differentiation in Arabidopsis named VISUAL-CC, which almost mimics the process of the SE-CC complex formation. Comparative expression analysis in VISUAL-CC reveals that SE and CC differentiation tends to show negative correlation, while total phloem differentiation is unchanged. This varying SE/CC ratio is largely dependent on GSK3 kinase activity. Indeed, gsk3 hextuple mutants possess many more SEs and fewer CCs, whereas gsk3 gain-of-function mutants partially increase the CC number. Taken together, GSK3 activity appears to function as a cell-fate switch in the phloem, thereby balancing the SE/CC ratio. Tamaki et al. develop VISUAL-CC to study SE-CC (sieve elements-companion cells) complex formation. They show that the balance in the SE/CC ratio is dependent on GSK3 activity using different genetic backgrounds. Their work provides insights on the role of GSK3 as a cell-fate switch in the phloem.