Browsing by Subject "MENDELIAN RANDOMIZATION"

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  • Rosenstrom, Tom; Fawcett, Tim W.; Higginson, Andrew D.; Metsa-Simola, Niina; Hagen, Edward H.; Houston, Alasdair I.; Martikainen, Pekka (2017)
    Divorce is associated with an increased probability of a depressive episode, but the causation of events remains unclear. Adaptive models of depression propose that depression is a social strategy in part, whereas non-adaptive models tend to propose a diathesis-stress mechanism. We compare an adaptive evolutionary model of depression to three alternative non-adaptive models with respect to their ability to explain the temporal pattern of depression around the time of divorce. Register-based data (304,112 individuals drawn from a random sample of 11% of Finnish people) on antidepressant purchases is used as a proxy for depression. This proxy affords an unprecedented temporal resolution (a 3-monthly prevalence estimates over 10 years) without any bias from non-compliance, and it can be linked with underlying episodes via a statistical model. The evolutionary-adaptation model (all time periods with risk of divorce are depressogenic) was the best quantitative description of the data. The non-adaptive stress-relief model (period before divorce is depressogenic and period afterwards is not) provided the second best quantitative description of the data. The peak-stress model (periods before and after divorce can be depressogenic) fit the data less well, and the stress-induction model (period following divorce is depressogenic and the preceding period is not) did not fit the data at all. The evolutionary model was the most detailed mechanistic description of the divorce-depression link among the models, and the best fit in terms of predicted curvature; thus, it offers most rigorous hypotheses for further study. The stress-relief model also fit very well and was the best model in a sensitivity analysis, encouraging development of more mechanistic models for that hypothesis.
  • Neuman, Manuela G.; French, Samuel W.; Zakhari, Samir; Malnick, Stephen; Seitz, Helmut K.; Cohen, Lawrence B.; Salaspuro, Mikko; Voinea-Griffin, Andreea; Barasch, Andrei; Kirpich, Irina A.; Thomes, Paul G.; Schrum, Laura W.; Donohue, Terrence M.; Kharbanda, Kusum K.; Cruz, Marcus; Opris, Mihai (2017)
    This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non alcohol -induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular.and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism. (C) 2017 Elsevier Inc. All rights reserved.
  • Korhonen, Päivi E.; Mikkola, Tuija; Kautiainen, Hannu; Eriksson, Johan G. (2021)
    High body mass index (BMI) is known to be associated with elevated blood pressure (BP). The present study aims to determine the relative importance of the two components of BMI, fat mass and lean body mass index, on BP levels. We assessed body composition with bioimpedance and performed 24 hour ambulatory BP measurements in 534 individuals (mean age 61 +/- 3 years) who had no cardiovascular medication. Fat mass index and lean mass index were calculated analogously to BMI as fat mass or lean body mass (kg) divided by the square of height (m2). Both fat mass index and lean mass index showed a positive, small to moderate relationship with all 24 hour BP components independently of age, sex, smoking, and leisure-time physical activity. There were no interaction effects between fat mass index and lean mass index on the mean BP levels. Adult lean body mass is a significant determinant of BP levels with an equal, albeit small to moderate magnitude as fat mass. Relatively high amount of muscle mass may not be beneficial to cardiovascular health.
  • Vogt, Susanne; Wahl, Simone; Kettunen, Johannes; Breitner, Susanne; Kastenmueller, Gabi; Gieger, Christian; Suhre, Karsten; Waldenberger, Melanie; Kratzsch, Juergen; Perola, Markus; Salomaa, Veikko; Blankenberg, Stefan; Zeller, Tanja; Soininen, Pasi; Kangas, Antti J.; Peters, Annette; Grallert, Harald; Ala-Korpela, Mika; Thorand, Barbara (2016)
    Background: Numerous observational studies have observed associations between vitamin D deficiency and cardiometabolic diseases, but these findings might be confounded by obesity. A characterization of the metabolic profile associated with serum 25-hydroxyvitamin D [25(OH)D] levels, in general and stratified by abdominal obesity, may help to untangle the relationship between vitamin D, obesity and cardiometabolic health. Methods: Serum metabolomics measurements were obtained from a nuclear magnetic resonance spectroscopy (NMR)- and a mass spectrometry (MS)-based platform. The discovery was conducted in 1726 participants of the population-based KORA-F4 study, in which the associations of the concentrations of 415 metabolites with 25(OH)D levels were assessed in linear models. The results were replicated in 6759 participants (NMR) and 609 (MS) participants, respectively, of the population-based FINRISK 1997 study. Results: Mean [standard deviation (SD)] 25(OH)D levels were 15.2 (7.5) ng/ml in KORA F4 and 13.8 (5.9) ng/ml in FINRISK 1997; 37 metabolites were associated with 25(OH) D in KORA F4 at P <0.05/415. Of these, 30 associations were replicated in FINRISK 1997 at P <0.05/37. Among these were constituents of (very) large very-low-density lipoprotein and small low-density lipoprotein subclasses and related measures like serum triglycerides as well as fatty acids and measures reflecting the degree of fatty acid saturation. The observed associations were independent of waist circumference and generally similar in abdominally obese and non-obese participants. Conclusions: Independently of abdominal obesity, higher 25(OH)D levels were associated with a metabolite profile characterized by lower concentrations of atherogenic lipids and a higher degree of fatty acid polyunsaturation. These results indicate that the relationship between vitamin D deficiency and cardiometabolic diseases is unlikely to merely reflect obesity-related pathomechanisms.
  • Felix, Janine F.; Joubert, Bonnie R.; Baccarelli, Andrea A.; Sharp, Gemma C.; Almqvist, Catarina; Annesi-Maesano, Isabella; Arshad, Hasan; Baiz, Nour; Bakermans-Kranenburg, Marian J.; Bakulski, Kelly M.; Binder, Elisabeth B.; Bouchard, Luigi; Breton, Carrie V.; Brunekreef, Bert; Brunst, Kelly J.; Burchard, Esteban G.; Bustamante, Mariona; Chatzi, Leda; Munthe-Kaas, Monica Cheng; Corpeleijn, Eva; Czamara, Darina; Dabelea, Dana; Smith, George Davey; De Boever, Patrick; Duijts, Liesbeth; Dwyer, Terence; Eng, Celeste; Eskenazi, Brenda; Everson, Todd M.; Falahi, Fahimeh; Fallin, M. Daniele; Farchi, Sara; Fernandez, Mariana F.; Gao, Lu; Gaunt, Tom R.; Ghantous, Akram; Gillman, Matthew W.; Gonseth, Semira; Grote, Veit; Gruzieva, Olena; Haberg, Siri E.; Herceg, Zdenko; Hivert, Marie-France; Holland, Nina; Holloway, John W.; Hoyo, Cathrine; Hu, Donglei; Huang, Rae-Chi; Huen, Karen; Jarvelin, Marjo-Riitta; Jima, Dereje D.; Just, Allan C.; Karagas, Margaret R.; Karlsson, Robert; Karmaus, Wilfried; Kechris, Katerina J.; Kere, Juha; Kogevinas, Manolis; Koletzko, Berthold; Koppelman, Gerard H.; Kupers, Leanne K.; Ladd-Acosta, Christine; Lahti, Jari; Lambrechts, Nathalie; Langie, Sabine A. S.; Lie, Rolv T.; Liu, Andrew H.; Magnus, Maria C.; Magnus, Per; Maguire, Rachel L.; Marsit, Carmen J.; McArdle, Wendy; Melen, Erik; Melton, Phillip; Murphy, Susan K.; Nawrot, Tim S.; Nistico, Lorenza; Nohr, Ellen A.; Nordlund, Bjorn; Nystad, Wenche; Oh, Sam S.; Oken, Emily; Page, Christian M.; Perron, Patrice; Pershagen, Goran; Pizzi, Costanza; Plusquin, Michelle; Räikkönen, Katri; Reese, Sarah E.; Reischl, Eva; Richiardi, Lorenzo; Ring, Susan; Roy, Ritu P.; Rzehak, Peter; Schoeters, Greet; Schwartz, David A.; Sebert, Sylvain; Snieder, Harold; Sorensen, Thorkild I. A.; Starling, Anne P.; Sunyer, Jordi; ATaylor, Jack; Tiemeier, Henning; Ullemar, Vilhelmina; Vafeiadi, Marina; Van Ijzendoorn, Marinus H.; Vonk, Judith M.; Vriens, Annette; Vrijheid, Martine; Wang, Pei; Wiemels, Joseph L.; Wilcox, Allen J.; Wright, Rosalind J.; Xu, Cheng-Jian; Xu, Zongli; Yang, Ivana V.; Yousefi, Paul; Zhang, Hongmei; Zhang, Weiming; Zhao, Shanshan; Agha, Golareh; Relton, Caroline L.; Jaddoe, Vincent W. V.; London, Stephanie J. (2018)
  • IPSYCH Grp; FinnGen Consortium; Fadista, Joao; Skotte, Line; Karjalainen, Juha; Abner, Erik; Sorensen, Erik; Ullum, Henrik; Werge, Thomas; Esko, Tonu; Milani, Lili; Palotie, Aarno; Daly, Mark; Melbye, Mads; Feenstra, Bjarke; Geller, Frank (2022)
    Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology. Hernias involve protrusion of an organ or tissue through its surrounding cavity. Here the authors carry out GWAS for five types of hernia and find 81 variants, most of which are associated with inguinal hernia; downstream analysis suggests an important role for connective tissue morphology.
  • Surendran, Praveen; Feofanova, Elena; Lahrouchi, Najim; Ntalla, Ioanna; Karthikeyan, Savita; Cook, James; Chen, Lingyan; Mifsud, Borbala; Yao, Chen; Kraja, Aldi T.; Cartwright, James H.; Hellwege, Jacklyn N.; Giri, Ayush; Tragante, Vinicius; Thorleifsson, Gudmar; Liu, Dajiang J.; Prins, Bram P.; Stewart, Isobel D.; Cabrera, Claudia P.; Eales, James M.; Akbarov, Artur; Auer, Paul L.; Bielak, Lawrence F.; Bis, Joshua C.; Braithwaite, Vickie S.; Brody, Jennifer A.; Daw, E. Warwick; Warren, Helen R.; Drenos, Fotios; Nielsen, Sune Fallgaard; Faul, Jessica D.; Fauman, Eric B.; Fava, Cristiano; Ferreira, Teresa; Foley, Christopher N.; Franceschini, Nora; Gao, He; Giannakopoulou, Olga; Giulianini, Franco; Gudbjartsson, Daniel F.; Guo, Xiuqing; Harris, Sarah E.; Havulinna, Aki S.; Helgadottir, Anna; Huffman, Jennifer E.; Hwang, Shih-Jen; Kanoni, Stavroula; Kontto, Jukka; Larson, Martin G.; Li-Gao, Ruifang; Lindström, Jaana; Lotta, Luca A.; Lu, Yingchang; Luan, Jian'an; Mahajan, Anubha; Malerba, Giovanni; Masca, Nicholas G. D.; Mei, Hao; Menni, Cristina; Mook-Kanamori, Dennis O.; Mosen-Ansorena, David; Muller-Nurasyid, Martina; Pare, Guillaume; Paul, Dirk S.; Perola, Markus; Poveda, Alaitz; Rauramaa, Rainer; Richard, Melissa; Richardson, Tom G.; Sepulveda, Nuno; Sim, Xueling; Smith, Albert; Smith, Jennifer A.; Staley, James R.; Stanakova, Alena; Sulem, Patrick; Theriault, Sebastien; Thorsteinsdottir, Unnur; Trompet, Stella; Varga, Tibor V.; Edwards, Digna R. Velez; Veronesi, Giovanni; Weiss, Stefan; Willems, Sara M.; Yao, Jie; Young, Robin; Yu, Bing; Zhang, Weihua; Zhao, Jing-Hua; Zhao, Wei; Zhao, Wei; Evangelou, Evangelos; Aeschbacher, Stefanie; Asllanaj, Eralda; Blankenberg, Stefan; Bonnycastle, Lori L.; Bork-Jensen, Jette; Brandslund, Ivan; Braund, Peter S.; Burgess, Stephen; Cho, Kelly; Christensen, Cramer; Connell, John; de Mutsert, Renee; Dominiczak, Anna F.; Dorr, Marcus; Eiriksdottir, Gudny; Farmaki, Aliki-Eleni; Gaziano, J. Michael; Grarup, Niels; Grove, Megan L.; Hallmans, Goran; Hansen, Torben; Have, Christian T.; Heiss, Gerardo; Jorgensen, Marit E.; Jousilahti, Pekka; Kajantie, Eero; Kamat, Mihir; Karajamaki, AnneMari; Karpe, Fredrik; Koistinen, Heikki A.; Kovesdy, Csaba P.; Kuulasmaa, Kari; Laatikainen, Tiina; Lannfelt, Lars; Lee, I-Te; Lee, Wen-Jane; Linneberg, Allan; Martin, Lisa W.; Moitry, Marie; Nadkarni, Girish; Neville, Matt J.; Palmer, Colin N. A.; Papanicolaou, George J.; Pedersen, Oluf; Peters, James; Poulter, Neil; Rasheed, Asif; Rasmussen, Katrine L.; Rayner, N. William; Magi, Reedik; Renstrom, Frida; Rettig, Rainer; Rossouw, Jacques; Schreiner, Pamela J.; Sever, Peter S.; Sigurdsson, Emil L.; Skaaby, Tea; Sun, Yan; Sundstrom, Johan; Thorgeirsson, Gudmundur; Esko, Tonu; Trabetti, Elisabetta; Tsao, Philip S.; Tuomi, Tiinamaija; Turner, Stephen T.; Tzoulaki, Ioanna; Vaartjes, Ilonca; Vergnaud, Anne-Claire; Willer, Cristen J.; Wilson, Peter W. F.; Witte, Daniel R.; Yonova-Doing, Ekaterina; Zhang, He; Aliya, Naheed; Almgren, Peter; Amouyel, Philippe; Asselbergs, Folkert W.; Barnes, Michael R.; Blakemore, Alexandra; Boehnke, Michael; Bots, Michiel L.; Bottinger, Erwin P.; Buring, Julie E.; Chambers, John C.; Chen, Yii-Der Ida; Chowdhury, Rajiv; Conen, David; Correa, Adolfo; Smith, George Davey; de Boer, Rudolf A.; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; Di Angelantonio, Emanuele; Elliott, Paul; Felix, Stephan B.; Ferrieres, Jean; Ford, Ian; Fornage, Myriam; Franks, Paul W.; Franks, Stephen; Frossard, Philippe; Gambaro, Giovanni; Gaunt, Tom R.; Groop, Leif; Gudnason, Vilmundur; Harris, Tamara B.; Hayward, Caroline; Hennig, Branwen J.; Herzig, Karl-Heinz; Ingelsson, Erik; Tuomilehto, Jaakko; Jarvelin, Marjo-Riitta; Jukema, J. Wouter; Kardia, Sharon L. R.; Kee, Frank; Kooner, Jaspal S.; Kooperberg, Charles; Launer, Lenore J.; Lind, Lars; Loos, Ruth J. F.; Majumder, Abdulla Al Shafi; Laakso, Markku; McCarthy, Mark; Melander, Olle; Mohlke, Karen L.; Murray, Alison D.; Nordestgaard, Borge Gronne; Orho-Melander, Marju; Packard, Chris J.; Padmanabhan, Sandosh; Palmas, Walter; Polasek, Ozren; Porteous, David J.; Prentice, Andrew M.; Province, Michael A.; Relton, Caroline L.; Rice, Kenneth; Ridker, Paul M.; Rolandsson, Olov; Rosendaal, Frits R.; Rotter, Jerome; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J.; Sattar, Naveed; Sheu, Wayne H-H; Smith, Blair H.; Soranzo, Nicole; Spector, Timothy D.; Starr, John M.; Sebert, Sylvain; Taylor, Kent D.; Lakka, Timo A.; Timpson, Nicholas J.; Tobin, Martin D.; van der Harst, Pim; van der Meer, Peter; Ramachandran, Vasan S.; Verweij, Niek; Virtamo, Jarmo; Volker, Uwe; Weir, David R.; Zeggini, Eleftheria; Charchar, Fadi J.; Wareham, Nicholas J.; Langenberg, Claudia; Tomaszewski, Maciej; Butterworth, Adam S.; Caulfield, Mark J.; Danesh, John; Edwards, Todd L.; Holm, Hilma; Hung, Adriana M.; Lindgren, Cecilia M.; Liu, Chunyu; Manning, Alisa K.; Morris, Andrew P.; Morrison, Alanna C.; O'Donnell, Christopher J.; Psaty, Bruce M.; Saleheen, Danish; Stefansson, Kari; Boerwinkle, Eric; Chasman, Daniel; Levy, Daniel; Newton-Cheh, Christopher; Munroe, Patricia B.; Howson, Joanna M. M. (2020)
    Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency
  • Wesolowska, Karolina; Elovainio, Marko; Hintsa, Taina; Jokela, Markus; Pulkki-Raback, Laura; Pitkänen, Niina; Lipsanen, Jari; Tukiainen, Janne; Lyytikäinen, Leo-Pekka; Lehtimäki, Terho; Juonala, Markus; Raitakari, Olli; Keltikangas-Järvinen, Liisa (2017)
    Type 2 diabetes (T2D) has been associated with depressive symptoms, but the causal direction of this association and the underlying mechanisms, such as increased glucose levels, remain unclear. We used instrumental-variable regression with a genetic instrument (Mendelian randomization) to examine a causal role of increased glucose concentrations in the development of depressive symptoms. Data were from the population-based Cardiovascular Risk in Young Finns Study (n = 1217). Depressive symptoms were assessed in 2012 using a modified Beck Depression Inventory (BDI-I). Fasting glucose was measured concurrently with depressive symptoms. A genetic risk score for fasting glucose (with 35 single nucleotide polymorphisms) was used as an instrumental variable for glucose. Glucose was not associated with depressive symptoms in the standard linear regression (B = -0.04, 95% CI [-0.12, 0.04], p = .34), but the instrumental-variable regression showed an inverse association between glucose and depressive symptoms (B = -0.43, 95% CI [-0.79, -0.07], p = .020). The difference between the estimates of standard linear regression and instrumental-variable regression was significant (p = .026) Our results suggest that the association between T2D and depressive symptoms is unlikely to be caused by increased glucose concentrations. It seems possible that T2D might be linked to depressive symptoms due to low glucose levels.
  • Li, Chen; Stoma, Svetlana; Lotta, Luca A.; Warner, Sophie; Albrecht, Eva; Allione, Alessandra; Arp, Pascal P.; Broer, Linda; Buxton, Jessica L.; Da Silva Couto Alves, Alexessander; Deelen, Joris; Fedko, Iryna O.; Gordon, Scott D.; Jiang, Tao; Karlsson, Robert; Kerrison, Nicola; Loe, Taylor K.; Mangino, Massimo; Milaneschi, Yuri; Miraglio, Benjamin; Pervjakova, Natalia; Russo, Alessia; Surakka, Ida; van der Spek, Ashley; Verhoeven, Josine E.; Amin, Najaf; Beekman, Marian; Blakemore, Alexandra I.; Canzian, Federico; Hamby, Stephen E.; Hottenga, Jouke-Jan; Jones, Peter D.; Jousilahti, Pekka; Mägi, Reedik; Medland, Sarah E.; Montgomery, Grant W.; Nyholt, Dale R.; Perola, Markus; Pietiläinen, Kirsi H.; Salomaa, Veikko; Sillanpää, Elina; Suchiman, H. Eka; van Heemst, Diana; Willemsen, Gonneke; Agudo, Antonio; Boeing, Heiner; Boomsma, Dorret I.; Chirlaque, Maria-Dolores; Fagherazzi, Guy; Ferrari, Pietro; Franks, Paul; Gieger, Christian; Eriksson, Johan Gunnar; Gunter, Marc; Hägg, Sara; Hovatta, Iiris; Imaz, Liher; Kaprio, Jaakko; Kaaks, Rudolf; Key, Timothy; Krogh, Vittorio; Martin, Nicholas G.; Melander, Olle; Metspalu, Andres; Moreno, Concha; Onland-Moret, N. Charlotte; Nilsson, Peter; Ong, Ken K.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Pedersen, Nancy L.; Penninx, Brenda W.J. H.; Quirós, J. Ramón; Jarvelin, Marjo Riitta; Rodríguez-Barranco, Miguel; Scott, Robert A.; Severi, Gianluca; Slagboom, P. Eline; Spector, Tim D.; Tjonneland, Anne; Trichopoulou, Antonia; Tumino, Rosario; Uitterlinden, André G.; van der Schouw, Yvonne T.; van Duijn, Cornelia M.; Weiderpass, Elisabete; Denchi, Eros Lazzerini; Matullo, Giuseppe; Butterworth, Adam S.; Danesh, John; Samani, Nilesh J.; Wareham, Nicholas J.; Nelson, Christopher P.; Langenberg, Claudia; Codd, Veryan (2020)
    Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) <0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
  • Genetics DNA Methylation Consort; NHLBI Trans-Omics Precision Med; McCartney, Daniel L.; Min, Josine L.; Richmond, Rebecca C.; Palviainen, Teemu; Ollikainen, Miina; Kaprio, Jaakko (2021)
    Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
  • FinnGen; Yin, Xianyong; Chan, Lap Sum; Bose, Debraj; Ripatti, Samuli; Palotie, Aarno; Boehnke, Michael (2022)
    The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms. Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.
  • BIOS Consortium; Min, Josine L.; Hemani, Gibran; Hannon, Eilis; Kumar, Ashish; Gupta, Richa; Bollepalli, Sailalitha; Mandaviya, Pooja; Ollikainen, Miina; Kaprio, Jaakko; Lahti, Jari (2021)
    DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs. Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
  • 23andMe Res Team; Subst Use Disorders Working Grp Ps; Int Cannabis Consortium (2018)
    Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested sub-stance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.
  • CREAM Consortium; Tedja, Milly S.; Haarman, Annechien E. G.; Meester-Smoor, Magda A.; Kaprio, Jaakko; Wedenoja, Juho (2019)
    The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.
  • Lemmelä, Susanna; Wigmore, Eleanor M.; Benner, Christian; Havulinna, Aki S.; Ong, Rachel M. Y.; Kempf, Tibor; Wollert, Kai C.; Blankenberg, Stefan; Zeller, Tanja; Peters, James E.; Salomaa, Veikko; Fritsch, Maria; March, Ruth; Palotie, Aarno; Daly, Mark; Butterworth, Adam S.; Kinnunen, Mervi; Paul, Dirk S.; Matakidou, Athena (2022)
    Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW p(FDR) = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.
  • Taylor, D. Leland; Jackson, Anne U.; Narisu, Narisu; Hemani, Gibran; Erdos, Michael R.; Chines, Peter S.; Swift, Amy; Idol, Jackie; Didion, John P.; Welch, Ryan P.; Kinnunen, Leena; Saramies, Jouko; Lakka, Timo A.; Laakso, Markku; Tuomilehto, Jaakko; Parker, Stephen C. J.; Koistinen, Heikki A.; Smith, George Davey; Boehnke, Michael; Scott, Laura J.; Birney, Ewan; Collins, Francis S. (2019)
    We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist-hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.
  • Beynon, Rhona A.; Richmond, Rebecca C.; Santos Ferreira, Diana L.; Ness, Andrew R.; May, Margaret; Davey Smith, George; Vincent, Emma E.; Adams, Charleen; Ala-Korpela, Mika; Würtz, Peter; Soidinsalo, Sebastian; Metcalfe, Christopher; Donovan, Jenny L.; Lane, Athene J.; Martin, Richard M. (2019)
    Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R-2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [beta (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (beta: -0.62; -1.03, -0.02; p = 0.004), pyruvate (beta: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (beta: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (beta: -0.65; -1.04, -0.26; p = 0.001 and beta: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.
  • Ference, Brian A.; Ginsberg, Henry N.; Graham, Ian; Ray, Kausik K.; Packard, Chris J.; Bruckert, Eric; Hegele, Robert A.; Krauss, Ronald M.; Raal, Frederick J.; Schunkert, Heribert; Watts, Gerald F.; Boren, Jan; Fazio, Sergio; Horton, Jay D.; Masana, Luis; Nicholls, Stephen J.; Nordestgaard, Borge G.; van de Sluis, Bart; Taskinen, Marja-Riitta; Tokgözoglu, Lale; Landmesser, Ulf; Laufs, Ulrich; Wiklund, Olov; Stock, Jane K.; Chapman, M. John; Catapano, Alberico L. (2017)
    Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
  • Cazaly, Emma; Saad, Joseph; Wang, Wenyu; Heckman, Caroline; Ollikainen, Miina; Tang, Jing (2019)
    Epigenetic research involves examining the mitotically heritable processes that regulate gene expression, independent of changes in the DNA sequence. Recent technical advances such as whole-genome bisulfite sequencing and affordable epigenomic array-based technologies, allow researchers to measure epigenetic profiles of large cohorts at a genome-wide level, generating comprehensive high-dimensional datasets that may contain important information for disease development and treatment opportunities. The epigenomic profile for a certain disease is often a result of the complex interplay between multiple genetic and environmental factors, which poses an enormous challenge to visualize and interpret these data. Furthermore, due to the dynamic nature of the epigenome, it is critical to determine causal relationships from the many correlated associations. In this review we provide an overview of recent data analysis approaches to integrate various omics layers to understand epigenetic mechanisms of complex diseases, such as obesity and cancer. We discuss the following topics: (i) advantages and limitations of major epigenetic profiling techniques, (ii) resources for standardization, annotation and harmonization of epigenetic data, and (iii) statistical methods and machine learning methods for establishing data-driven hypotheses of key regulatory mechanisms. Finally, we discuss the future directions for data integration that shall facilitate the discovery of epigenetic-based biomarkers and therapies.
  • EGG Consortium (2019)
    Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.