Browsing by Subject "LOCI"

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  • 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)
  • 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)
  • Prokic, Ivana; Lahousse, Lies; de Vries, Maaike; Liu, Jun; Kalaoja, Marita; Vonk, Judith M.; van der Plaat, Diana A.; van Diemen, Cleo C.; van der Spek, Ashley; Zhernakova, Alexandra; Fu, Jingyuan; Ghanbari, Mohsen; Ala-Korpela, Mika; Kettunen, Johannes; Havulinna, Aki S.; Perola, Markus; Salomaa, Veikko; Lind, Lars; Arnlov, Johan; Stricker, Bruno H. C.; Brusselle, Guy G.; Boezen, H. Marike; van Duijn, Cornelia M.; Amin, Najaf (2020)
    Background Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. Methods We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. Results There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16,P = 5.6 x 10(- 4)in the discovery and OR = 1.30,P = 1.8 x 10(- 6)in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20). Conclusions Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.
  • van Zuydam, Natalie R.; Ahlqvist, Emma; Sandholm, Niina; Deshmukh, Harshal; Rayner, N. William; Abdalla, Moustafa; Ladenvall, Claes; Ziemek, Daniel; Fauman, Eric; Robertson, Neil R.; McKeigue, Paul M.; Valo, Erkka; Forsblom, Carol; Harjutsalo, Valma; Perna, Annalisa; Rurali, Erica; Marcovecchio, M. Loredana; Igo, Robert P.; Salem, Rany M.; Perico, Norberto; Lajer, Maria; Karajamak, Annemari; Imamura, Minako; Kubo, Michiaki; Takahashi, Atsushi; Sim, Xueling; Liu, Jianjun; van Dam, Rob M.; Jiang, Guozhi; Tam, Claudia H. T.; Luk, Andrea O. Y.; Lee, Heung Man; Lim, Cadmon K. P.; Szeto, Cheuk Chun; So, Wing Yee; Chan, Juliana C. N.; Ang, Su Fen; Dorajoo, Rajkumar; Wang, Ling; Clara, Tan Si Hua; McKnight, Amy-Jayne; Duffy, Seamus; Pezzolesi, Marcus G.; Marre, Michel; Gyorgy, Beata; Hadjadj, Samy; Hiraki, Linda T.; Tuomi, Tiinamaija; Groop, Per-Henrik; Groop, Leif C. (2018)
    dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
  • Int Headache Genetics Consortium; 23andMe Res Team; Guo, Yanjun; Rist, Pamela M.; Daghlas, Iyas; Giulianini, Franco; Kurth, Tobias; Chasman, Daniel; Artto, Ville; Färkkilä, Markus; Kallela, Mikko; Pärn, Kalle; Muona, Mikko; Sarin, Antti-Pekka; Kaunisto, Mari; Hämäläinen, Eija; Kaprio, Jaakko; Palta, Priit; Wessman, Maija; Palotie, Aarno; Vepsäläinen, Salli; Wedenoja, Juho; Eriksson, Johan G.; Heikkilä, Kauko (2020)
    Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N-cases/N-controls = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r(g) = 0.11, P = 3.56 x 10(-06)) and systolic BP (SBP, r(g) = 0.06, P = 0.01), but not pulse pressure (PP, r(g) = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P
  • 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)
  • van der Valk, Ralf J. P.; Kreiner-Moller, Eskil; Kooijman, Marjolein N.; Guxens, Monica; Stergiakouli, Evangelia; Saaf, Annika; Bradfield, Jonathan P.; Geller, Frank; Hayes, M. Geoffrey; Cousminer, Diana L.; Koerner, Antje; Thiering, Elisabeth; Curtin, John A.; Myhre, Ronny; Huikari, Ville; Joro, Raimo; Kerkhof, Marjan; Warrington, Nicole M.; Pitkanen, Niina; Ntalla, Ioanna; Horikoshi, Momoko; Veijola, Riitta; Freathy, Rachel M.; Teo, Yik-Ying; Barton, Sheila J.; Evans, David M.; Kemp, John P.; St Pourcain, Beate; Ring, Susan M.; Smith, George Davey; Bergstrom, Anna; Kull, Inger; Hakonarson, Hakon; Mentch, Frank D.; Bisgaard, Hans; Chawes, Bo; Stokholm, Jakob; Waage, Johannes; Eriksen, Patrick; Sevelsted, Astrid; Melbye, Mads; van Duijn, Cornelia M.; Medina-Gomez, Carolina; Hofman, Albert; de Jongste, Johan C.; Taal, H. Rob; Eriksson, Johan; Palotie, Aarno; Knip, Mikael; Widen, Elisabeth; Early Genetics Lifecourse; Genetic Invest ANthropometric; Early Growth Genetics EGG (2015)
  • Ahluwalia, Tarunveer S.; Schulz, Christina-Alexandra; Waage, Johannes; Skaaby, Tea; Sandholm, Niina; van Zuydam, Natalie; Charmet, Romain; Bork-Jensen, Jette; Almgren, Peter; Thuesen, Betina H.; Bedin, Mathilda; Brandslund, Ivan; Christensen, Cramer K.; Linneberg, Allan; Ahlqvist, Emma; Groop, Per-Henrik; Hadjadj, Samy; Tregouet, David-Alexandre; Jorgensen, Marit E.; Grarup, Niels; Pedersen, Oluf; Simons, Matias; Groop, Leif; Orho-Melander, Marju; McCarthy, Mark I.; Melander, Olle; Rossing, Peter; Kilpeläinen, Tuomas O.; Hansen, Torben (2019)
    Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, =0.27, p=1.3x10(-11)) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p(interaction)=7.0x10(-4), with diabetes=0.69, without diabetes=0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p(Bonferroni)
  • Nuotio, Marja-Liisa; Pervjakova, Natalia; Joensuu, Anni; Karhunen, Ville; Hiekkalinna, Tero; Milani, Lili; Kettunen, Johannes; Järvelin, Marjo-Riitta; Jousilahti, Pekka; Metspalu, Andres; Salomaa, Veikko; Kristiansson, Kati; Perola, Markus (2020)
    The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P=1.80x10(-8)). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P=5.36x10(-9)) and waist circumference (P=5.21x10(-9)). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P=2.24x10(-7)). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P=7.81x10(-8)). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.
  • Hannon, Eilis; Dempster, Emma; Viana, Joana; Burrage, Joe; Smith, Adam R.; Macdonald, Ruby; St Clair, David; Mustard, Colette; Breen, Gerome; Therman, Sebastian; Kaprio, Jaakko; Toulopoulou, Timothea; Pol, Hilleke E. Hulshoff; Bohlken, Marc M.; Kahn, Rene S.; Nenadic, Igor; Hultman, Christina M.; Murray, Robin M.; Collier, David A.; Bass, Nick; Gurling, Hugh; McQuillin, Andrew; Schalkwyk, Leonard; Mill, Jonathan (2016)
    Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
  • 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
  • Gandolfi, Barbara; Alhaddad, Hasan; Abdi, Mona; Bach, Leslie H.; Creighton, Erica K.; Davis, Brian W.; Decker, Jared E.; Dodman, Nicholas H.; Grahn, Jennifer C.; Grahn, Robert A.; Haase, Bianca; Haggstrom, Jens; Hamilton, Michael J.; Helps, Christopher R.; Kurushima, Jennifer D.; Lohi, Hannes; Longeri, Maria; Malik, Richard; Meurs, Kathryn M.; Montague, Michael J.; Mullikin, James C.; Murphy, William J.; Nilson, Sara M.; Pedersen, Niels C.; Peterson, Carlyn B.; Rusbridge, Clare; Saif, Rashid; Shelton, G. Diane; Warren, Wesley C.; Wasim, Muhammad; Lyons, Leslie A. (2018)
    The development of high throughput SNP genotyping technologies has improved the genetic dissection of simple and complex traits in many species including cats. The properties of feline 62,897 SNPs Illumina Infinium iSelect DNA array are described using a dataset of over 2,000 feline samples, the most extensive to date, representing 41 cat breeds, a random bred population, and four wild felid species. Accuracy and efficiency of the array's genotypes and its utility in performing population-based analyses were evaluated. Average marker distance across the array was 37,741 Kb, and across the dataset, only 1% (625) of the markers exhibited poor genotyping and only 0.35% (221) showed Mendelian errors. Marker polymorphism varied across cat breeds and the average minor allele frequency (MAF) of all markers across domestic cats was 0.21. Population structure analysis confirmed a Western to Eastern structural continuum of cat breeds. Genome-wide linkage disequilibrium ranged from 50-1,500 Kb for domestic cats and 750 Kb for European wildcats (Felis silvestris silvestris). Array use in trait association mapping was investigated under different modes of inheritance, selection and population sizes. The efficient array design and cat genotype dataset continues to advance the understanding of cat breeds and will support monogenic health studies across feline breeds and populations.
  • NBCS Collaborators; ABCTB Investigators; kConFab Investigators; Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Muranen, Taru A.; Nevanlinna, Heli (2021)
    Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
  • Leinonen, Jaakko T.; Surakka, Ida; Havulinna, Aki S.; Kettunen, Johannes; Luoto, Riitta; Salomaa, Veikko; Widen, Elisabeth (2012)
  • Clark, David W.; Okada, Yukinori; Moore, Kristjan H. S.; Mason, Dan; Pirastu, Nicola; Gandin, Ilaria; Mattsson, Hannele; Barnes, Catriona L. K.; Lin, Kuang; Zhao, Jing Hua; Deelen, Patrick; Rohde, Rebecca; Schurmann, Claudia; Guo, Xiuqing; Giulianini, Franco; Zhang, Weihua; Medina-Gomez, Carolina; Karlsson, Robert; Bao, Yanchun; Bartz, Traci M.; Baumbach, Clemens; Biino, Ginevra; Bixley, Matthew J.; Brumat, Marco; Chai, Jin-Fang; Corre, Tanguy; Cousminer, Diana L.; Dekker, Annelot M.; Eccles, David A.; Van Eijk, Kristel R.; Fuchsberger, Christian; Gao, He; Germain, Marine; Gordon, Scott D.; de Haan, Hugoline G.; Harris, Sarah E.; Hofer, Edith; Huerta-Chagoya, Alicia; Igartua, Catherine; Jansen, Iris E.; Jia, Yucheng; Kacprowski, Tim; Karlsson, Torgny; Kleber, Marcus E.; Li, Shengchao Alfred; Li-Gao, Ruifang; Mahajan, Anubha; Matsuda, Koichi; Meidtner, Karina; Meng, Weihua; Montasser, May E.; van der Most, Peter J.; Munz, Matthias; Nutile, Teresa; Palviainen, Teemu; Prasad, Gauri; Prasad, Rashmi B.; Priyanka, Tallapragada Divya Sri; Rizzi, Federica; Salvi, Erika; Sapkota, Bishwa R.; Shriner, Daniel; Skotte, Line; Smart, Melissa C.; Smith, Albert Vernon; van der Spek, Ashley; Spracklen, Cassandra N.; Strawbridge, Rona J.; Tajuddin, Salman M.; Trompet, Stella; Turman, Constance; Verweij, Niek; Viberti, Clara; Wang, Lihua; Warren, Helen R.; Wootton, Robyn E.; Yanek, Lisa R.; Yao, Jie; Yousri, Noha A.; Zhao, Wei; Adeyemo, Adebowale A.; Afaq, Saima; Alberto Aguilar-Salinas, Carlos; Akiyama, Masato; Albert, Matthew L.; Allison, Matthew A.; Alver, Maris; Aung, Tin; Azizi, Fereidoun; Bentley, Amy R.; Boeing, Heiner; Boerwinkle, Eric; Borja, Judith B.; de Borst, Gert J.; Bottinger, Erwin P.; Broer, Linda; Campbell, Harry; Chanock, Stephen; Chee, Miao-Li; Chen, Guanjie; Chen, Yii-Der I.; Chen, Zhengming; Chiu, Yen-Feng; Cocca, Massimiliano; Collins, Francis S.; Concas, Maria Pina; Corley, Janie; Cugliari, Giovanni; Van Dam, Rob M.; Damulina, Anna; Daneshpour, Maryam S.; Day, Felix R.; Delgado, Graciela E.; Dhana, Klodian; Doney, Alexander S. F.; Doerr, Marcus; Doumatey, Ayo P.; Dzimiri, Nduna; Ebenesersdottir, S. Sunna; Elliott, Joshua; Elliott, Paul; Ewert, Ralf; Felix, Janine F.; Fischer, Krista; Freedman, Barry I.; Girotto, Giorgia; Goel, Anuj; Gogele, Martin; Goodarzi, Mark O.; Graff, Mariaelisa; Granot-Hershkovitz, Einat; Grodstein, Francine; Guarrera, Simonetta; Gudbjartsson, Daniel F.; Guity, Kamran; Gunnarsson, Bjarni; Guo, Yu; Hagenaars, Saskia P.; Haiman, Christopher A.; Halevy, Avner; Harris, Tamara B.; Hedayati, Mehdi; van Heel, David A.; Hirata, Makoto; Hofer, Imo; Hsiung, Chao Agnes; Huang, Jinyan; Hung, Yi-Jen; Ikram, M. Arfan; Jagadeesan, Anuradha; Jousilahti, Pekka; Kamatani, Yoichiro; Kanai, Masahiro; Kerrison, Nicola D.; Kessler, Thorsten; Khaw, Kay-Tee; Khor, Chiea Chuen; de Kleijn, Dominique P. V.; Koh, Woon-Puay; Kolcic, Ivana; Kraft, Peter; Kramer, Bernhard K.; Kutalik, Zoltan; Kuusisto, Johanna; Langenberg, Claudia; Launer, Lenore J.; Lawlor, Deborah A.; Lee, I-Te; Lee, Wen-Jane; Lerch, Markus M.; Li, Liming; Liu, Jianjun; Loh, Marie; London, Stephanie J.; Loomis, Stephanie; Lu, Yingchang; Luan, Jian'an; Magi, Reedik; Manichaikul, Ani W.; Manunta, Paolo; Masson, Gisli; Matoba, Nana; Mei, Xue W.; Meisinger, Christa; Meitinger, Thomas; Mezzavilla, Massimo; Milani, Lili; Millwood, Iona Y.; Momozawa, Yukihide; Moore, Amy; Morange, Pierre-Emmanuel; Moreno-Macias, Hortensia; Mori, Trevor A.; Morrison, Alanna C.; Muka, Taulant; Murakami, Yoshinori; Murray, Alison D.; de Mutsert, Renee; Mychaleckyj, Josyf C.; Nalls, Mike A.; Nauck, Matthias; Neville, Matt J.; Nolte, Ilja M.; Ong, Ken K.; Orozco, Lorena; Padmanabhan, Sandosh; Palsson, Gunnar; Pankow, James S.; Pattaro, Cristian; Pattie, Alison; Polasek, Ozren; Poulter, Neil; Pramstaller, Peter P.; Quintana-Murci, Lluis; Räikkönen, Katri; Ralhan, Sarju; Rao, Dabeeru C.; van Rheenen, Wouter; Rich, Stephen S.; Ridker, Paul M.; Rietveld, Cornelius A.; Robino, Antonietta; van Rooij, Frank J. A.; Ruggiero, Daniela; Saba, Yasaman; Sabanayagam, Charumathi; Sabater-Lleal, Maria; Felicita Sala, Cinzia; Salomaa, Veikko; Sandow, Kevin; Schmidt, Helena; Scott, Laura J.; Scott, William R.; Sedaghati-Khayat, Bahareh; Sennblad, Bengt; van Setten, Jessica; Sever, Peter J.; Sheu, Wayne H-H; Shi, Yuan; Shrestha, Smeeta; Shukla, Sharvari Rahul; Sigurdsson, Jon K.; Sikka, Timo Tonis; Singh, Jai Rup; Smith, Blair H.; Stancakova, Alena; Stanton, Alice; Starr, John M.; Stefansdottir, Lilja; Straker, Leon; Sulem, Patrick; Sveinbjornsson, Gardar; Swertz, Morris A.; Taylor, Adele M.; Taylor, Kent D.; Terzikhan, Natalie; Tham, Yih-Chung; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tillander, Annika; Tracy, Russell P.; Tusie-Luna, Teresa; Tzoulaki, Ioanna; Vaccargiu, Simona; Vangipurapu, Jagadish; Veldink, Jan H.; Vitart, Veronique; Volker, Uwe; Vuoksimaa, Eero; Wakil, Salma M.; Waldenberger, Melanie; Wander, Gurpreet S.; Wang, Ya Xing; Wareham, Nicholas J.; Wild, Sarah; Yajnik, Chittaranjan S.; Yuan, Jian-Min; Zeng, Lingyao; Zhang, Liang; Zhou, Jie; Amin, Najaf; Asselbergs, Folkert W.; Bakker, Stephan J. L.; Becker, Diane M.; Lehne, Benjamin; Bennett, David A.; van den Berg, Leonard H.; Berndt, Sonja I.; Bharadwaj, Dwaipayan; Bielak, Lawrence F.; Bochud, Murielle; Boehnke, Mike; Bouchard, Claude; Bradfield, Jonathan P.; Brody, Jennifer A.; Campbell, Archie; Carmi, Shai; Caulfield, Mark J.; Cesarini, David; Chambers, John C.; Chandak, Giriraj Ratan; Cheng, Ching-Yu; Ciullo, Marina; Cornelis, Marilyn; Cusi, Daniele; Smith, George Davey; Deary, Ian J.; Dorajoo, Rajkumar; van Duijn, Cornelia M.; Ellinghaus, David; Erdmann, Jeanette; Eriksson, Johan G.; Evangelou, Evangelos; Evans, Michele K.; Faul, Jessica D.; Feenstra, Bjarke; Feitosa, Mary; Foisy, Sylvain; Franke, Andre; Friedlander, Yechiel; Gasparini, Paolo; Gieger, Christian; Gonzalez, Clicerio; Goyette, Philippe; Grant, Struan F. A.; Griffiths, Lyn R.; Groop, Leif; Gudnason, Vilmundur; Gyllensten, Ulf; Hakonarson, Hakon; Hamsten, Anders; van der Harst, Pim; Heng, Chew-Kiat; Hicks, Andrew A.; Hochner, Hagit; Huikuri, Heikki; Hunt, Steven C.; Jaddoe, Vincent W. V.; De Jager, Philip L.; Johannesson, Magnus; Johansson, Asa; Jonas, Jost B.; Jukema, J. Wouter; Junttila, Juhani; Kaprio, Jaakko; Kardia, Sharon L. R.; Karpe, Fredrik; Kumari, Meena; Laakso, Markku; van der Laan, Sander W.; Lahti, Jari; Laudes, Matthias; Lea, Rodney A.; Lieb, Wolfgang; Lumley, Thomas; Martin, Nicholas G.; Marz, Winfried; Matullo, Giuseppe; McCarthy, Mark I.; Medland, Sarah E.; Merriman, Tony R.; Metspalu, Andres; Meyer, Brian F.; Mohlke, Karen L.; Montgomery, Grant W.; Mook-Kanamori, Dennis; Munroe, Patricia B.; North, Kari E.; Nyholt, Dale R.; O'connell, Jeffery R.; Ober, Carole; Oldehinkel, Albertine J.; Palmas, Walter; Palmer, Colin; Pasterkamp, Gerard G.; Patin, Etienne; Pennell, Craig E.; Perusse, Louis; Peyser, Patricia A.; Pirastu, Mario; Polderman, Tinca J. C.; Porteous, David J.; Posthuma, Danielle; Psaty, Bruce M.; Rioux, John D.; Rivadeneira, Fernando; Rotimi, Charles; Rotter, Jerome I.; Rudan, Igor; Den Ruijter, Hester M.; Sanghera, Dharambir K.; Sattar, Naveed; Schmidt, Reinhold; Schulze, Matthias B.; Schunkert, Heribert; Scott, Robert A.; Shuldiner, Alan R.; Sim, Xueling; Small, Neil; Smith, Jennifer A.; Sotoodehnia, Nona; Tai, E-Shyong; Teumer, Alexander; Timpson, Nicholas J.; Toniolo, Daniela; Tregouet, David-Alexandre; Tuomi, Tiinamaija; Vollenweider, Peter; Wang, Carol A.; Weir, David R.; Whitfield, John B.; Wijmenga, Cisca; Wong, Tien-Yin; Wright, John; Yang, Jingyun; Yu, Lei; Zemel, Babette S.; Zonderman, Alan B.; Perola, Markus; Magnusson, Patrik K. E.; Uitterlinden, Andre G.; Kooner, Jaspal S.; Chasman, Daniel I.; Loos, Ruth J. F.; Franceschini, Nora; Franke, Lude; Haley, Chris S.; Hayward, Caroline; Walters, Robin G.; Perry, John R. B.; Esko, Tonu; Helgason, Agnar; Stefansson, Kari; Joshi, Peter K.; Kubo, Michiaki; Wilson, James F. (2019)
    In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.
  • Peltola, Tomi; Marttinen, Pekka; Jula, Antti; Salomaa, Veikko; Perola, Markus; Vehtari, Aki (2012)
  • Pers, Tune H.; Karjalainen, Juha M.; Chan, Yingleong; Westra, Harm-Jan; Wood, Andrew R.; Yang, Jian; Lui, Julian C.; Vedantam, Sailaja; Gustafsson, Stefan; Esko, Tonu; Frayling, Tim; Speliotes, Elizabeth K.; Boehnke, Michael; Raychaudhuri, Soumya; Fehrmann, Rudolf S. N.; Hirschhorn, Joel N.; Franke, Lude; Genetic Invest ANthropometric Trai; Kaprio, Jaakko (2015)
    The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.
  • Verta, Jukka-Pekka; Debes, Paul; Piavchenko, Nikolai; Ruokolainen, Annukka; Ovaskainen, Outi Sinikka; Moustakas-Verho, Jacqueline; Tillanen, Seija Iiris; Parre, Noora; Aykanat, Tutku; Erkinaro, Jaakko; Primmer, Craig (2020)
    A major goal in biology is to understand how evolution shapes variation in individual life histories. Genome-wide association studies have been successful in uncovering genome regions linked with traits underlying life history variation in a range of species. However, lack of functional studies of the discovered genotype-phenotype associations severely restrains our understanding how alternative life history traits evolved and are mediated at the molecular level. Here, we report acis-regulatory mechanism whereby expression of alternative isoforms of the transcription co-factorvestigial-like 3(vgll3) associate with variation in a key life history trait, age at maturity, in Atlantic salmon (Salmo salar). Using a common-garden experiment, we first show thatvgll3genotype associates with puberty timing in one-year-old salmon males. By way of temporal sampling ofvgll3expression in ten tissues across the first year of salmon development, we identify a pubertal transition invgll3expression where maturation coincided with a 66% reduction in testicularvgll3expression. Thelatematuration allele was not only associated with a tendency to delay puberty, but also with expression of a rare transcript isoform ofvgll3pre-puberty. By comparing absolutevgll3mRNA copies in heterozygotes we show that the expression difference between theearlyandlatematurity alleles is largelycis-regulatory. We propose a model whereby expression of a rare isoform from thelateallele shifts the liability of its carriers towards delaying puberty. These results exemplify the potential importance of regulatory differences as a mechanism for the evolution of life history traits. Author summary Alternative life history strategies are an important source of diversity within populations and promote the maintenance of adaptive capacity and population resilience. However, in many cases the molecular basis of different life history strategies remains elusive. Age at maturity is a key adaptive life history trait in Atlantic salmon and has a relatively simple genetic basis. Using salmon age at maturity as a model, we report a mechanism whereby different transcript isoforms of the key age at maturity gene,vestigial-like 3(vgll3), associate with variation in the timing of male puberty. Our results show how gene regulatory differences in conjunction with variation in gene transcript structure can encode for complex alternative life histories.
  • Yu, Hongyao; Frank, Christoph; Sundquist, Jan; Hemminki, Akseli; Hemminki, Kari (2017)
    Background It has been proposed that cancer is more common in some families than in others, but the hypothesis lacks population level support. We use a novel approach by studying any cancers in large three-generation families and thus are able to find risks even though penetrance is low. Methods Individuals in the nation-wide Swedish Family-Cancer Database were organised in three generations and the relative risk (RR) of cancer was calculated to the persons in the third generation by the numbers of patients with cancer in generations 1, 2 and 3. Results The RRs for any cancer in generation 3 increased by the numbers of affected relatives, reaching 1.61 when at least seven relatives were diagnosed. The median patient had two affected relatives, and 7.0% had five or more affected relatives with an RR of 1.46, which translated to an absolute risk of 21.5% compared with 14.7% in population by age 65 years. For prostate cancer, the RR was 2.85 with four or more affected family members with any cancer, and it increased to 14.42 with four or more concordant cancers in family members. RRs for prostate cancer were approximately equal (2.70 vs 2.85) if a man had one relative with prostate cancer or four or more relatives diagnosed with any cancer. Conclusions A strong family history of cancer, regardless of tumour type, increases cancer risk of family members and calls for mechanistic explanations. Our data provide tools for counselling of patients with cancer with both low and high familiar risks.
  • Howard, Sasha R.; Guasti, Leonardo; Poliandri, Ariel; David, Alessia; Cabrera, Claudia P.; Barnes, Michael R.; Wehkalampi, Karoliina; O'Rahilly, Stephen; Aiken, Catherine E.; Coll, Anthony P.; Ma, Marcella; Rimmington, Debra; Yeo, Giles S. H.; Dunkel, Leo (2018)
    Context: Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures: We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients: We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. Results: We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p. Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto(+/-) mice displayed a significantly delayed timing of pubertal onset (P <0.05). Conclusions: Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.