Browsing by Subject "LD SCORE REGRESSION"

Sort by: Order: Results:

Now showing items 1-18 of 18
  • Xie, Aoji; Ensink, Elizabeth; Li, Peipei; Gordevicius, Juozas; Marshall, Lee L.; George, Sonia; Pospisilik, John Andrew; Aho, Velma T. E.; Houser, Madelyn C.; Pereira, Pedro A. B.; Rudi, Knut; Paulin, Lars; Tansey, Malu G.; Auvinen, Petri; Brundin, Patrik; Brundin, Lena; Labrie, Viviane; Scheperjans, Filip (2022)
    Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
  • 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.
  • AMP-T2D-GENES Consortia; Goodrich, Julia K.; Groop, Leif; Koistinen, Heikki A.; Tuomi, Tiinamaija; Tuomilehto, Jaakko (2021)
    Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias. Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.
  • ADHD Working Grp Psychiat Genomics; Early Lifecourse Genetic; 23andMe Res Team; Daly, Mark J. (2019)
    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
  • SpiroMeta Consortium; Int COPD Genetics Consortium; Understanding Soc Sci Grp (2019)
    Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P <5 x 10(-8); 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
  • GoLEAD Consortium; SUMMIT Consortium; van Zuydam, Natalie R.; Stiby, Alexander; Abdalla, Moustafa; Dahlström, Emma H.; Vlachopoulou, Efthymia; Sandholm, Niina; Forsblom, Carol; Sinisalo, Juha; Perola, Markus; Kallio, Milla; Groop, Per-Henrik; Groop, Leif; Kullo, Iftikhar J. (2021)
    Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (P-association
  • Int League Against Epilepsy Conso; Abou-Khalil, Bassel; Eriksson, Johan G.; Lehesjoki, Anna-Elina; Palotie, Aarno (2018)
    The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
  • Jansen, Ris E.; van der Lee, Sven J.; Gomez-Fonseca, Duber; de Rojas, Itziar; Dalmasso, Maria Carolina; Grenier-Boley, Benjamin; Zettergren, Anna; Mishra, Aniket; Ali, Muhammad; Andrade, Victor; Bellenguez, Celine; Kleineidam, Luca; Kucukali, Fahri; Sung, Yun Ju; Tesi, Niccolo; Vromen, Ellen M.; Wightman, Douglas P.; Alcolea, Daniel; Alegret, Montserrat; Alvarez, Ignacio; Amouyel, Philippe; Athanasiu, Lavinia; Bahrami, Shahram; Bailly, Henri; Belbin, Olivia; Bergh, Sverre; Bertram, Lars; Biessels, Geert Jan; Blennow, Kaj; Blesa, Rafael; Boada, Merce; Boland, Anne; Buerger, Katharina; Carracedo, Angel; Cervera-Carles, Laura; Chene, Genevieve; Claassen, Jurgen A. H. R.; Debette, Stephanie; Deleuze, Jean-Francois; de Deyn, Peter Paul; Diehl-Schmid, Janine; Djurovic, Srdjan; Dols-Icardo, Oriol; Dufouil, Carole; Duron, Emmanuelle; Duezel, Emrah; Fladby, Tormod; Fortea, Juan; Froelich, Lutz; Garcia-Gonzalez, Pablo; Garcia-Martinez, Maria; Giegling, Ina; Goldhardt, Oliver; Gobom, Johan; Grimmer, Timo; Haapasalo, Annakaisa; Hampel, Harald; Hanon, Olivier; Hausner, Lucrezia; Heilmann-Heimbach, Stefanie; Helisalmi, Seppo; Heneka, Michael T.; Hernandez, Isabel; Herukka, Sanna-Kaisa; Holstege, Henne; Jarholm, Jonas; Kern, Silke; Knapskog, Anne-Brita; Koivisto, Anne M.; Kornhuber, Johannes; Kuulasmaa, Teemu; Lage, Carmen; Laske, Christoph; Leinonen, Ville; Lewczuk, Piotr; Lleo, Alberto; de Munain, Adolfo Lopez; Lopez-Garcia, Sara; Maier, Wolfgang; Marquie, Marta; Mol, Merel O.; Montrreal, Laura; Moreno, Fermin; Moreno-Grau, Sonia; Nicolas, Gael; Nothen, Markus M.; Orellana, Adelina; Palhaugen, Lene; Papma, Janne M.; Pasquier, Florence; Perneczky, Robert; Peters, Oliver; Pijnenburg, Yolande A. L.; Popp, Julius; Posthuma, Danielle; Pozueta, Ana; Priller, Josef; Puerta, Raquel; Quintela, Ines; Ramakers, Inez; Rodriguez-Rodriguez, Eloy; Rujescu, Dan; Saltvedt, Ingvild; Sanchez-Juan, Pascual; Scheltens, Philip; Scherbaum, Norbert; Schmid, Matthias; Schneider, Anja; Selbaek, Geir; Selnes, Per; Shadrin, Alexey; Skoog, Ingmar; Soininen, Hilkka; Tarraga, Lluis; Teipel, Stefan; Tijms, Betty; Tsolaki, Magda; Van Broeckhoven, Christine; Van Dongen, Jasper; van Swieten, John C.; Vandenberghe, Rik; Vidal, Jean-Sebastien; Visser, Pieter J.; Vogelgsang, Jonathan; Waern, Margda; Wagner, Michael; Wiltfang, Jens; Wittens, Mandy M. J.; Zetterberg, Henrik; Zulaica, Miren; van Duijn, Cornelia M.; Bjerke, Maria; Engelborghs, Sebastiaan; Jessen, Frank; Teunissen, Charlotte E.; Pastor, Pau; Hiltunen, Mikko; Ingelsson, Martin; Andreassen, Ole A.; Clarimon, Jordi; Sleegers, Kristel; Ruiz, Agustin; Ramirez, Alfredo; Cruchaga, Carlos; Lambert, Jean-Charles; van der Flier, Wiesje (2022)
    Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
  • Psychiat Genomics Consortium; BUPGEN; 23andMe Res Team; Grove, Jakob; Ripke, Stephan; Als, Thomas D.; Palotie, Aarno; Daly, Mark J. (2019)
    Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
  • Lam, Max; Trampush, Joey W.; Yu, Jin; Knowles, Emma; Davies, Gail; Liewald, David C.; Starr, John M.; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J.; Steen, Vidar M.; Espeseth, Thomas; Raikkonen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G.; Giegling, Ina; Konte, Bettina; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E.; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Attix, Deborah K.; Need, Anna C.; Cirulli, Elizabeth T.; Voineskos, Aristotle N.; Stefanis, Nikos C.; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Arking, Dan E.; Smyrnis, Nikolaos; Bilder, Robert M.; Freimer, Nelson A.; Cannon, Tyrone D.; London, Edythe; Poldrack, Russell A.; Sabb, Fred W.; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A.; Dickinson, Dwight; Straub, Richard E.; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R.; Weinberger, Daniel R.; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Le Hellard, Stephanie; Keller, Matthew C.; Andreassen, Ole A.; Deary, Ian J.; Glahn, David C.; Malhotra, Anil K.; Lencz, Todd (2017)
    Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g''), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
  • UK10K Consortium (2019)
    Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
  • 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.
  • Erzurumluoglu, A. Mesut; Liu, Mengzhen; Jackson, Victoria E.; Barnes, Daniel R.; Datta, Gargi; Melbourne, Carl A.; Young, Robin; Batini, Chiara; Surendran, Praveen; Jiang, Tao; Adnan, Sheikh Daud; Afaq, Saima; Agrawal, Arpana; Altmaier, Elisabeth; Antoniou, Antonis C.; Asselbergs, Folkert W.; Baumbach, Clemens; Bierut, Laura; Bertelsen, Sarah; Boehnke, Michael; Bots, Michiel L.; Brazel, David M.; Chambers, John C.; Chang-Claude, Jenny; Chen, Chu; Corley, Janie; Chou, Yi-Ling; David, Sean P.; de Boer, Rudolf A.; de Leeuw, Christiaan A.; Dennis, Joe G.; Dominiczak, Anna F.; Dunning, Alison M.; Easton, Douglas F.; Eaton, Charles; Elliott, Paul; Evangelou, Evangelos; Faul, Jessica D.; Foroud, Tatiana; Goate, Alison; Gong, Jian; Grabe, Hans J.; Haessler, Jeff; Haiman, Christopher; Hallmans, Goran; Hammerschlag, Anke R.; Harris, Sarah E.; Hattersley, Andrew; Heath, Andrew; Hsu, Chris; Iacono, William G.; Kanoni, Stavroula; Kapoor, Manav; Kaprio, Jaakko; Kardia, Sharon L.; Karpe, Fredrik; Kontto, Jukka; Kooner, Jaspal S.; Kooperberg, Charles; Kuulasmaa, Kari; Laakso, Markku; Lai, Dongbing; Langenberg, Claudia; Le, Nhung; Lettre, Guillaume; Loukola, Anu; Luan, Jian'an; Madden, Pamela A. F.; Mangino, Massimo; Marioni, Riccardo E.; Marouli, Eirini; Marten, Jonathan; Martin, Nicholas G.; McGue, Matt; Michailidou, Kyriaki; Mihailov, Evelin; Moayyeri, Alireza; Moitry, Marie; Mueller-Nurasyid, Martina; Naheed, Aliya; Nauck, Matthias; Neville, Matthew J.; Nielsen, Sune Fallgaard; North, Kari; Perola, Markus; Pharoah, Paul D. P.; Pistis, Giorgio; Polderman, Tinca J.; Posthuma, Danielle; Poulter, Neil; Qaiser, Beenish; Rasheed, Asif; Reiner, Alex; Renstrom, Frida; Rice, John; Rohde, Rebecca; Rolandsson, Olov; Samani, Nilesh J.; Samuel, Maria; Schlessinger, David; Scholte, Steven H.; Scott, Robert A.; Sever, Peter; Shao, Yaming; Shrine, Nick; Smith, Jennifer A.; Starr, John M.; Stirrups, Kathleen; Stram, Danielle; Stringham, Heather M.; Tachmazidou, Ioanna; Tardif, Jean-Claude; Thompson, Deborah J.; Tindle, Hilary A.; Tragante, Vinicius; Trompet, Stella; Turcot, Valerie; Tyrrell, Jessica; Vaartjes, Ilonca; van der Leij, Andries R.; van der Meer, Peter; Varga, Tibor V.; Verweij, Niek; Voelzke, Henry; Wareham, Nicholas J.; Warren, Helen R.; Weir, David R.; Weiss, Stefan; Wetherill, Leah; Yaghootkar, Hanieh; Yavas, Ersin; Jiang, Yu; Chen, Fang; Zhan, Xiaowei; Zhang, Weihua; Zhao, Wei; Zhao, Wei; Zhou, Kaixin; Amouyel, Philippe; Blankenberg, Stefan; Caulfield, Mark J.; Chowdhury, Rajiv; Cucca, Francesco; Deary, Ian J.; Deloukas, Panos; Di Angelantonio, Emanuele; Ferrario, Marco; Ferrieres, Jean; Franks, Paul W.; Frayling, Tim M.; Frossard, Philippe; Hall, Ian P.; Hayward, Caroline; Jansson, Jan-Hakan; Jukema, J. Wouter; Kee, Frank; Männistö, Satu; Metspalu, Andres; Munroe, Patricia B.; Nordestgaard, Borge Gronne; Palmer, Colin N. A.; Salomaa, Veikko; Sattar, Naveed; Spector, Timothy; Strachan, David Peter; van der Harst, Pim; Zeggini, Eleftheria; Saleheen, Danish; Butterworth, Adam S.; Wain, Louise V.; Abecasis, Goncalo R.; Danesh, John; Tobin, Martin D.; Vrieze, Scott; Liu, Dajiang J.; Howson, Joanna M. M. (2020)
    Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations withP <5 x 10(-8)in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P <5 x 10(-8)) in the discovery samples. Ten novel SNVs, including rs12616219 nearTMEM182, were followed-up and five of them (rs462779 inREV3L, rs12780116 inCNNM2, rs1190736 inGPR101, rs11539157 inPJA1, and rs12616219 nearTMEM182) replicated at a Bonferroni significance threshold (P <4.5 x 10(-3)) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, inCCDC141and two low-frequency SNVs inCEP350andHDGFRP2. Functional follow-up implied that decreased expression ofREV3Lmay lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
  • ITALSGEN Consortium; Int ALS Genomics Consortium; Bandres-Ciga, Sara; Tienari, Pentti J. (2019)
    Objective To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation Here, we have developed a public resource () which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481
  • Early Genetics Lifecourse; EGG Consortium; EGG Membership; EAGLE Membership; Middeldorp, Christel M.; Mahajan, Anubha; Auvinen, Juha; Eriksson, Johan G.; Groop, Leif; Kaprio, Jaakko; Lahti, Jari; Palviainen, Teemu; Strandberg, Timo; Vuoksimaa, Eero; Widen, Elisabeth E. (2019)
    The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
  • 23andMe Res Team; Räikkönen, Katri (2018)
    Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
  • Liu, Xueping; Helenius, Dorte; Skotte, Line; Beaumont, Robin N.; Wielscher, Matthias; Geller, Frank; Juodakis, Julius; Mahajan, Anubha; Bradfield, Jonathan P.; Lin, Frederick Tj; Vogelezang, Suzanne; Bustamante, Mariona; Ahluwalia, Tarunveer S.; Pitkanen, Niina; Wang, Carol A.; Bacelis, Jonas; Borges, Maria C.; Zhang, Ge; Bedell, Bruce A.; Rossi, Robert M.; Skogstrand, Kristin; Peng, Shouneng; Thompson, Wesley K.; Appadurai, Vivek; Lawlor, Debbie A.; Kalliala, Ilkka; Power, Christine; McCarthy, Mark; Boyd, Heather A.; Marazita, Mary L.; Hakonarson, Hakon; Hayes, M. Geoffrey; Scholtens, Denise M.; Rivadeneira, Fernando; Jaddoe, Vincent W. V.; Vinding, Rebecca K.; Bisgaard, Hans; Knight, Bridget A.; Pahkala, Katja; Raitakari, Olli; Helgeland, Oyvind; Johansson, Stefan; Njolstad, Pal R.; Fadista, Joao; Schork, Andrew J.; Nudel, Ron; Miller, Daniel E.; Chen, Xiaoting; Weirauch, Matthew T.; Mortensen, Preben Bo; Borglum, Anders D.; Nordentoft, Merete; Mors, Ole; Hao, Ke; Ryckman, Kelli K.; Hougaard, David M.; Kottyan, Leah C.; Pennell, Craig E.; Lyytikainen, Leo-Pekka; Bonnelykke, Klaus; Vrijheid, Martine; Felix, Janine F.; Lowe, William L.; Grant, Struan Fa; Hypponen, Elina; Jacobsson, Bo; Jarvelin, Marjo-Riitta; Muglia, Louis J.; Murray, Jeffrey C.; Freathy, Rachel M.; Werge, Thomas M.; Melbye, Mads; Buil, Alfonso; Feenstra, Bjarke (2019)
    The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P= 3.96 x 10(-14)). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
  • CORtisol Network CORNET Consortium; Crawford, Andrew A.; Bankier, Sean; Altmaier, Elisabeth; Lahti, Jari; Eriksson, Johan; Walker, Brian R. (2021)
    The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from similar to 2.2 M to similar to 7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and alpha 1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.